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Valacyclovir

PubChem CID
135398742
Structure
Valacyclovir_small.png
Valacyclovir_3D_Structure.png
Molecular Formula
Synonyms
  • valacyclovir
  • Valaciclovir
  • 124832-26-4
  • ValACV
  • Zelitrex
Molecular Weight
324.34 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2019-01-15
  • Modify:
    2025-01-18
Description
Valacyclovir is a L-valyl ester. It has a role as an antiviral drug. It is functionally related to a guanine.
Valaciclovir (valacyclovir), also known as Valtrex, is an antiviral drug that has been used to manage and treat various herpes infections for more than 2 decades. It was initially approved by the FDA in 1995 and marketed by GlaxoSmithKline. Valacyclovir is the L-valine ester of aciclovir. It is a member of the purine (guanine) nucleoside analog drug class. This class of drugs forms an important part of hepatitis, HIV, and cytomegalovirus drug regimens. One major use of valacyclovir is the treatment of genital herpes episodes or outbreaks. Genital herpes is a frequently diagnosed sexually transmitted disease which currently affects more than 400 million individuals worldwide. It is caused by infection with the herpes simplex virus (HSV). Infection with this virus is lifelong with periodic episodes of reactivation.
Valacyclovir is a Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpes Zoster Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor. The mechanism of action of valacyclovir is as a DNA Polymerase Inhibitor.
See also: Acyclovir (has active moiety); Valacyclovir Hydrochloride (has salt form); Valacyclovir hydrochloride monohydrate (active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Valacyclovir.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 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
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

HDOVUKNUBWVHOX-QMMMGPOBSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

CC(C)[C@@H](C(=O)OCCOCN1C=NC2=C1N=C(NC2=O)N)N
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C13H20N6O4
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

124832-27-5

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 Wikidata

2.3.14 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)ethyl L-valinate
  • 256U87
  • Acyclovir, L valyl Ester
  • acyclovir, L-valyl ester
  • BW256U87
  • D- Valacyclovir
  • L Valylacyclovir
  • L-valyl Ester Acyclovir
  • L-valylacyclovir
  • valaciclovir
  • valacyclovir
  • valacyclovir hydrochloride
  • valacyclovir hydrochloride, (DL)-isomer
  • valacyclovir, (D)-isomer
  • valacyclovir, (DL)-isomer
  • valacyclovir, (L)-isomer
  • Valacyclovir, D-
  • valacyclovir, x-hydrochloride, (D)-isomer
  • valacyclovir, x-hydrochloride, (DL)-isomer
  • Valtrex

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
324.34 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3-AA
Property Value
-0.9
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
324.15460314 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
324.15460314 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
147 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
23
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
483
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Melting Point

3.2.3 Solubility

174 mg/mL at 25 degrees Celsius
Crystalline solid, occurs as hydrate. UV max (water): 252.8 nm (e 8530). Solubility in water: 174 mg/mL /Valacyclovir hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1702
3.55e+00 g/L

3.2.4 LogP

-0.3
-0.3

3.2.5 Dissociation Constants

3.2.6 Collision Cross Section

164.19 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

166.89 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.7 Other Experimental Properties

White to off-white powder. MW: 360.09; maximum solubility in water at 25 °C: 174 mg/mL; pKa1 1.90; pKa2 7.47; pKa3 9.43 /Valacyclovir hydrochloride/
Physicians Desk Reference 66th ed. PDR Network, LLC, Montvale, NJ. p. 1367 (2012)

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents
Antiherpes medicines

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 MS-MS

1 of 3
View All
Spectra ID
Ionization Mode
positive
Top 5 Peaks

152.055618 100

135.027756 37.83

146.116974 15.29

144.103165 7.77

67.901878 7.64

Thumbnail
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Notes
instrument=qTof
2 of 3
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

152.0562 100

72.08053 17.74

135.0295 10.59

84.08189 7.78

146.11731 6.32

Thumbnail
Thumbnail

4.1.2 LC-MS

1 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
323.147
Instrument
Thermo Q Exactive HF
Instrument Type
LC-ESI-QFT
Ionization Mode
negative
Collision Energy
HCD (NCE 20-30-40%)
Retention Time
6.82995
Top 5 Peaks

116.07042 100

176.05684 25.82

323.14694 21.14

206.06767 14.54

162.04108 3.88

Thumbnail
Thumbnail
2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
325.1621
Instrument
SCIEX TripleTOF 6600
Instrument Type
LC-ESI-QTOF
Ionization Mode
positive
Collision Energy
35 eV
Retention Time
6.564583
Top 5 Peaks

152.0562 100

72.08053 17.74

135.0295 10.59

84.08189 7.78

146.11731 6.32

Thumbnail
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for: **Adults** • Cold Sores (Herpes Labialis) • Genital Herpes • Treatment of genital herpes lesions in immunocompetent patients (initial or recurrent episode) • Suppression of genital herpes lesions in immunocompetent or HIV-infected patients • Reduction of viral transmission • Herpes Zoster **Pediatric Patients** • Cold Sores (Herpes Labialis) • Chickenpox **Limitations of use** The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients.

7.2 LiverTox Summary

Valacyclovir is a nucleoside analogue antiviral agent and prodrug of acyclovir which is used in therapy of herpes simplex and varicella-zoster virus infections. Valacyclovir has been associated with rare instances mild, clinically apparent liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents
Antiviral Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Antiherpes medicines
Formulation
Indication
(1) Zoster; (2) Varicella; (3) Herpes simplex infections

7.5 FDA National Drug Code Directory

7.6 Drug Labels

Drug and label

7.7 Clinical Trials

7.7.1 ClinicalTrials.gov

7.7.2 EU Clinical Trials Register

7.7.3 NIPH Clinical Trials Search of Japan

7.8 Therapeutic Uses

Antiviral Agents
National Library of Medicine's Medical Subject Headings online file (MeSH, 2012)
Oral valacyclovir is used in the treatment of initial episodes of genital herpes simplex virus (HSV-2) infection in immunocompetent adults and adolescents. Because many patients with first episodes of genital herpes present with mild clinical symptoms but later develop severe or prolonged symptoms, the US Centers for Disease Control and Prevention (CDC) states that most patients with initial genital herpes should receive antiviral therapy. /Included in US product labeling/
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 842
Oral valacyclovir is used in the treatment of recurrent episodes of genital herpes in immunocompetent adults and adolescents. Antiviral therapy for recurrent genital herpes can be given episodically to ameliorate or shorten the duration of lesions or can be given continuously as suppressive therapy to reduce the frequency of recurrences. /Included in US product labeling/
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 842
Valacyclovir is used for the episodic treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in adults and adolescents. /Included in US product labeling/
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 843
For more Therapeutic Uses (Complete) data for Valacyclovir (9 total), please visit the HSDB record page.

7.9 Drug Warnings

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valtrex at doses of 8 grams per day. Treatment with Valtrex should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
There are no adequate and well-controlled studies of Valtrex or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Valtrex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
Cases of acute renal failure have been reported in: 1. Elderly patients with or without reduced renal function. Caution should be exercised when administering Valtrex to geriatric patients, and dosage reduction is recommended for those with impaired renal function. 2. Patients with underlying renal disease who received higher than recommended doses of Valtrex for their level of renal function. Dosage reduction is recommended when administering Valtrex to patients with renal impairment. 3. Patients receiving other nephrotoxic drugs. Caution should be exercised when administering Valtrex to patients receiving potentially nephrotoxic drugs. 4. Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
The most common adverse reactions reported in at least 1 indication by greater than 10% of adult patients treated with Valtrex and observed more frequently with Valtrex compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric patients aged less than 18 years was headache.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
For more Drug Warnings (Complete) data for Valacyclovir (8 total), please visit the HSDB record page.

7.10 Drug Tolerance

Resistance of herpes simplex virus (HSV) and varicella-zoster virus (VZV) to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered. Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

**Antiviral effects** Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors. **Clinical study results** For the various conditions below, clinical study results are summarized as follows: _Cold sores_ Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration. _Initial genital herpes episodes_ 643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days. _Recurrent genital herpes episodes_ The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding. These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration. **A note on resistance** The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases.

8.2 MeSH Pharmacological Classification

Antiviral Agents
Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
MZ1IW7Q79D
Active Moiety
VALACYCLOVIR
Pharmacological Classes
Mechanisms of Action [MoA] - DNA Polymerase Inhibitors
Pharmacological Classes
Established Pharmacologic Class [EPC] - Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor
Pharmacological Classes
Established Pharmacologic Class [EPC] - Herpes Zoster Virus Nucleoside Analog DNA Polymerase Inhibitor
Pharmacological Classes
Established Pharmacologic Class [EPC] - Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor
Pharmacological Classes
Nucleoside Analog [EXT]
FDA Pharmacology Summary
Valacyclovir is a Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpes Zoster Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor. The mechanism of action of valacyclovir is as a DNA Polymerase Inhibitor.
2 of 2
Non-Proprietary Name
VALACYCLOVIR
Pharmacological Classes
DNA Polymerase Inhibitors [MoA]; Nucleoside Analog [EXT]; Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor [EPC]; Herpes Zoster Virus Nucleoside Analog DNA Polymerase Inhibitor [EPC]; Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor [EPC]

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AB - Nucleosides and nucleotides excl. reverse transcriptase inhibitors

J05AB11 - Valaciclovir

8.5 Absorption, Distribution and Excretion

Absorption
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food.
Route of Elimination
After oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was measured in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine.
Volume of Distribution
Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma AUC ratio, is approximately 25% for aciclovir and the metabolite _8-hydroxy-aciclovir_ (8-OH-ACV), and approximately 2.5% for the metabolite _9-(carboxymethoxy)methylguanine_. In a study of immunocompromised pediatric patients, the volume of distribution of a 15 ml/kg dose of valacyclovir was 1.34 ± 0.65 L/kg.
Clearance
Renal clearance of acyclovir following the administration of a single 1 gram dose of valacylcovir to 12 healthy 437 volunteers was approximately 255 ± 86 mL/min, which represents 42% of total acyclovir apparent plasma clearance.
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. The absolute bioavailability of acyclovir after administration of Valtrex is 54.5% + or - 9.1% as determined following a 1-gram oral dose of Valtrex and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valtrex is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of Valtrex to 12 healthy volunteers was approximately 255 + or - 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
The mechanism of intestinal transport of valacyclovir, the L-valyl ester prodrug of acyclovir, was investigated in rats using an in situ intestinal perfusion technique. Results showed that the oral bioavailability of valacyclovir appears to be significantly influenced by the preabsorptive conversion of valacyclovir to the poorly absorbed acyclovir, by the involvement of multiple transporters in valacyclovir small-intestinal uptake, and by the low permeability of valacyclovir in the colon.
Sinko PJ, Balimane PV; Biopharm Drug Dispos 19 (May): 209-17 (1998)
Following oral administration of a 500 mg dose of VALTREX to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of VALTREX twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

8.6 Metabolism / Metabolites

Valacyclovir is converted to acyclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Acyclovir is also transformed, to a small extent, to inactive metabolites by _aldehyde oxidase_ in addition to _alcohol dehydrogenase_ and _aldehyde dehydrogenase_. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes.
... Aciclovir's main metabolite /is/ 9-carboxymethoxymethylguanine. ...
Hellden A et al; J Antimicrob Chemother 57 (5): 945-9 (2006)
Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 ug/mL at all doses. After single-dose administration of 1 gram of Valtrex, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 ug/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

8.7 Biological Half-Life

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function.
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of Valtrex in volunteers with normal renal function.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

8.8 Mechanism of Action

Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme _valacyclovir hydrolase_. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form. The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral _thymidine kinase_ (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for _thymidine kinase_ (TK). In summary, the antiviral effects of valacyclovir are achieved in 3 ways: 1) competitive inhibition of viral DNA polymerase 2) incorporation and termination of the growing viral DNA chain 3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK).
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in cell culture and in vivo. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Cytoplasm
  • Membrane

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

MEDICATION

Use (kg; approx.) in Germany (2009): >750

Use (kg) in USA (2002): 63500

Consumption (g per capita; approx.) in Germany (2009): 0.00916

Consumption (g per capita) in the USA (2002): 0.225

Excretion rate: 0.01

Calculated removal (%): 22

9.2 Methods of Manufacturing

Preparation: T.A. Krenitsky et al., EP 308065; L.M. Beauchamp, US 4957924 (1989, 1990 both to Wellcome)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1702

9.3 Formulations / Preparations

Table: Valacyclovir Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
500 mg (of valacyclovir)
Brand or Generic Name (Manufacturer)
Valtrex Caplets (GlaxoSmithKline)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
1 g (of valacyclovir)
Brand or Generic Name (Manufacturer)
Valtrex Caplets (GlaxoSmithKline)
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 845

10 Identification

10.1 Clinical Laboratory Methods

Liquid chromatography/tandem mass spectrometry
Swati J et al; Int J of Environ Sci 1 (7): 1526-1541 (2011)
High performance liquid chromatography
Swati J et al; Int J of Environ Sci 1 (7): 1526-1541 (2011)
UV Spectrophotometry
Swati J et al; Int J of Environ Sci 1 (7): 1526-1541 (2011)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements
H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P317, P330, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary
The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (100%)

11.2 Accidental Release Measures

11.2.1 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

11.3 Handling and Storage

11.3.1 Storage Conditions

Store at 15 deg to 25 °C (59 deg to 77 °F). Dispense in a well-closed container as defined in the USP.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

11.4 Regulatory Information

11.4.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including valacyclovir hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Valacyclovir hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of November 21, 2012: https://www.fda.gov/cder/ob/

12 Toxicity

12.1 Toxicological Information

12.1.1 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Valacyclovir
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.2 Hepatotoxicity

Oral therapy with valacyclovir is associated with a low rate of mild-to-moderate serum aminotransferase elevations, but these abnormalities are usually asymptomatic and self-limited even with continuation of therapy. Complicating the attribution of liver test abnormalities to valacyclovir therapy is the fact that enzyme elevations are not uncommon during the course of varicella-zoster infection (both chickenpox and shingles) and can progress to clinically apparent hepatitis and even acute liver failure. Clinically apparent liver disease due to valacyclovir itself is rare, but isolated reports have been published. The time to onset was short (1 to 2 weeks) and the course mild, with few symptoms and rapid resolution (Case 1). The pattern of liver injury described was mixed hepatocellular-cholestatic. Immunoallergic features and autoantibodies were absent.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
valaciclovir
DILI Annotation
Less-DILI-Concern
Severity Grade
3
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

The dosage of acyclovir in milk after valacyclovir is less than 1% of a typical infant dosage and would not be expected to cause any adverse effects in breastfed infants. No special precautions are required when using valacyclovir during breastfeeding. In one study, administration of valacyclovir to mothers with concurrent herpes simplex type 2 and HIV infections reduced breastmilk shedding of the HIV virus in breastmilk at 6 and 14 weeks postpartum, but not later. In another study in HIV-positive mothers, valacyclovir did not reduced breastmilk shedding of cytomegalovirus (CMV) or infant CMV acquisition.

◉ Effects in Breastfed Infants

In a study of pregnant women with concurrent HIV and Herpes simplex infections, mothers received zidovudine 300 mg daily from week of pregnancy until 12 months postpartum and nevirapine at delivery. Half of the women (n = 74) also received valacyclovir 500 mg orally twice daily from 34 weeks gestation until 12 months postpartum. At 6 weeks postpartum, all infants who received acyclovir in breastmilk had normal serum creatinine (<0.83 mg/dL). Their median serum creatinine and alanine aminotransferase (ALT) values, and growth were no different from those of unexposed infants, with the exception of one infant with an ALT level of 70.1 units/L. Infants whose mothers received valacyclovir generally had adverse effects that were similar to the placebo group, except that treated infants had a lower risk of eczema and oral thrush than infants in the placebo arm.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.5 Interactions

Concomitant use of valacyclovir and probenecid may increase peak plasma concentrations and AUC of acyclovir. This pharmacokinetic interaction is not considered clinically important in patients with normal renal function and no dosage adjustments are necessary in these patients.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 844
Concomitant use of valacyclovir and cimetidine may increase peak plasma concentrations and AUC of acyclovir. This pharmacokinetic interaction is not considered clinically important in patients with normal renal function; no dosage adjustments are necessary in these patients.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 844
Mycophenolate mofetil (MMF) is a drug which decreases the frequency of renal transplantation rejection. However, cytomegalovirus infections are a common feature of this treatment leading the physicians to prescribe antiviral prophylactic drugs like valacyclovir. During this association, neutropenia occur and the cause of this adverse effect is difficult to define. This report presents a case of neutropenia in a woman treated with MMF and valacyclovir. As the duration of the valacyclovir treatment exactly corresponds to the neutropenia duration, and the mycophenolate trough levels increased with the neutrophil count, the responsibility of this neutropenia was ascribed to valacyclovir. However, an examination of the literature for cases of neutropenia led to the suspicion of an interaction between MMF and valacyclovir. Mycophenolate may increase intracellular concentrations of valacyclovir up to hematotoxic levels. This mechanism may explain the interaction and further research is needed to confirm this interaction.
Royer B et al; Clin Transplant 17 (2): 158-61 (2003)

12.1.6 Antidote and Emergency Treatment

Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. /Antiviral and antiretroviral agents/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126
Specific drugs and antidotes: There are no specific antidotes for these agents. Anecdotal cases of patients with severe lactic acidosis suggest that vitamin deficiency may be a contributor to the development of a life-threatening condition. Riboflavin ... and/or thiamine ... may be beneficial if levels are low. /Antiviral and antiretroviral agents/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126
Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antiviral and antiretroviral agents/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
For more Antidote and Emergency Treatment (Complete) data for Valacyclovir (7 total), please visit the HSDB record page.

12.1.7 Human Toxicity Excerpts

/CASE REPORTS/ Drug-related eruptions that appear only on intertriginous or flexural folds and in gluteal areas have recently been termed symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). We report a case of a 56-year-old woman with acute erythematous rash in the intertriginous areas after treatment with the L-valine ester of acyclovir, valacyclovir. Oral-challenge tests resulted in erythematous pruritic rash in the intertriginous area by valacyclovir. The patient was diagnosed as having SDRIFE due to valacyclovir.
Daito J et al; Dermatology 218 (1): 60-2 (2009)
/CASE REPORTS/ ... Toxicity caused by valacyclovir in a patient on hemodialysis /is reported/. After initial recuperation resulting from treatment with hemodialysis, the patient experienced a relapse of neurologic symptoms, again necessitating hemodialysis. Although acyclovir and its analogues are generally safe drugs, they should be used with caution in patients with end-stage renal disease. Therapeutic drug monitoring may be indicated.
Linssen-Schuurmans CD et al; Ther Drug Monit 20 (4): 385-6 (1998)
/CASE REPORTS/ ... Three cases of neurotoxicity in patients with renal failure, treated with Zelitrex (valacyclovir) /is reported/. The patients are two women and a man, aged 76 +/- 4.6 years, who presented acute mental confusion during a treatment with valacyclovir. In two cases, the patients previously had altered renal function and were under peritoneal dialysis. In the last case, the patient had simultaneous neurotoxicity and acute renal failure. After the discontinuation of the drug, the outcome was favourable in all cases. /These/ cases focus attention on the possible neurotoxicity of valacyclovir, which is an amino acid ester prodrug of acyclovir, rapidly and almost completely hydrolysed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir and may account for unexpected overdoses, which may lead to serious neurological toxicity.
Peyriere H et al; Rev Med Interne 22 (3): 297-303 (2001)
/CASE REPORTS/ The patient was a 67-year-old man with a 2-year history of peritoneal dialysis for end-stage renal disease due to hypertensive nephropathy. He presented to a dermatologist with a complaint of pain in the right femoral region. He was diagnosed as having herpes zoster and valacyclovir, 1,000 mg/day, was prescribed. After 5 days of taking valacyclovir orally, he felt fretful and hallucinations appeared. He was admitted to our hospital and was hospitalized in our urology ward. We diagnosed his condition as neurotoxicity caused by an overdose of valacyclovir. As his general condition was stable, he was treated only by continuation of peritoneal dialysis. After 7 days of hospitalization, the neurotoxicity completely disappeared and he left the hospital. His serum acyclovir concentration at admission was 20.20 ug/L, and was reduced to 0.7 ug/L when he left the hospital. This supported our diagnosis of valacyclovir-induced neurotoxicity. In this case, valacyclovir should have been reduced to 500 mg/day, considering his renal function. Although we could treat the patient only by continuation of peritoneal dialysis, hemodialysis seems to be an effective treatment method in the case of unstable general condition or severe adverse effects, because it can eliminate the serum acyclovir.
Takayanagi A et al; Hinyokika Kiyo 56 (11): 617-9 (2010)
For more Human Toxicity Excerpts (Complete) data for Valacyclovir (10 total), please visit the HSDB record page.

12.1.8 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
/GENOTOXICITY/ An Ames assay was negative in the absence or presence of metabolic activation. Also negative was ... a rat cytogenetic study. In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was mutagenic in a mouse micronucleus assay.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719
/VETERINARY CASE REPORTS/ To determine whether orally administered valacyclovir can be used safely and effectively to treat cats with primary, feline herpesvirus 1 (FHV-1) infection, 14 specific-pathogen-free adult cats ... were infected with FHV-1 strain 87-727 (300 microliters, 10(7) plaque-forming units/ml) by ocular and nasal inoculations, and were treated every 6 hours with dextrose (controls) or valacyclovir (60 mg/kg of body weight, PO). Virus shedding from both eyes and the oropharynx was monitored every 2 days by virus isolation, and subjective clinical scores were assigned daily for ocular and nasal discharge and conjunctival hyperemia. Urinalysis, CBC, and serum biochemical analysis were done prior to inoculation, and on days 2, 5, 7, 9, and 12 of infection. Differences in CBC and serum biochemical indices between groups were compared, as were differences between preinfection values and maximal postinfection values, rectal temperature, and scores for disease severity. All cats developed acute conjunctivitis and rhinitis typical of FHV-1 infection. Beginning between days 6 and 9, valacyclovir-treated cats became noticeably more lethargic and dehydrated than did cats of the control group. Total WBC and neutrophil counts were significantly lower in cats of the valacyclovir group. The experiment was terminated on day 12 for humane reasons. Histologic changes attributable to FHV-1 infection were similar in all cats. Additional histologic abnormalities seen only in the valacyclovir-treated cats were coagulative necrosis of the renal tubular epithelium, centrilobular atrophy and hepatic necrosis, and severe bone marrow depression. Cats appear to be uniquely sensitive to the toxic effects of valacyclovir, and even high doses appear not to suppress FHV-1 replication in acutely infected cats. Use of valacyclovir is of questionable value in cats with acute FHV-1 infection and, at high doses, the drug may be toxic.
Nasisse MP et al; Am J Vet Res. 1997 Oct;58(10):1141-4 (1997)

12.1.9 Populations at Special Risk

...The elderly with impaired renal function seem to be the most susceptible group to valacyclovir neurotoxicity. ...
Pipili C et al; Ren Fail. 2012 Nov 26. (Epub ahead of print)
Cases of acute renal failure have been reported in: 1. Elderly patients with or without reduced renal function. Caution should be exercised when administering Valtrex to geriatric patients, and dosage reduction is recommended for those with impaired renal function. 2. Patients with underlying renal disease who received higher than recommended doses of Valtrex for their level of renal function. Dosage reduction is recommended when administering Valtrex to patients with renal impairment.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

12.1.10 Protein Binding

The binding of valacyclovir to human plasma proteins is low and ranges from 13.5% to 17.9%.

12.2 Ecological Information

12.2.1 Environmental Water Concentrations

Valacyclovir is one of the antiviral drugs designated as emerging pollutants as, when consumed, they may be largely unchanged and raise questions for their removal from water and wastewater(1).
(1) Swati J et al; Int J Environ Sci 1: 1526-1541 (2011). Available from, as of Jan 21, 2013: https://www.ipublishing.co.in/jesvol1no12010/EIJES2100.pdf

12.2.2 Milk Concentrations

Following oral administration of a 500 mg dose of VALTREX to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of VALTREX twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine.
US Natl Inst Health; DailyMed. Current Medication Information for VALTREX (valacyclovir hydrochloride) tablet, film coated (December 2011). Available from, as of November 25, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

Take with or without food.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Drug Groups

18.6 KEGG : Antimicrobials

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 ChEMBL Target Tree

18.11 UN GHS Classification

18.12 NORMAN Suspect List Exchange Classification

18.13 CCSBase Classification

18.14 EPA DSSTox Classification

18.15 EPA Substance Registry Services Tree

18.16 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    L-Valine, 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)methoxy)ethyl ester
    https://echa.europa.eu/substance-information/-/substanceinfo/100.114.479
    L-Valine, 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)methoxy)ethyl ester (EC: 603-015-6)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/40436
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  9. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  10. ChEBI
  11. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  12. LiverTox
  13. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  14. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  15. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  16. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  17. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  18. Therapeutic Target Database (TTD)
  19. DailyMed
  20. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. Drugs and Lactation Database (LactMed)
  22. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  23. EU Clinical Trials Register
  24. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  25. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    VALACICLOVIR
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  26. Japan Chemical Substance Dictionary (Nikkaji)
  27. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
  28. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  29. Metabolomics Workbench
  30. NIPH Clinical Trials Search of Japan
  31. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
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    https://www.whocc.no/copyright_disclaimer/
  32. Protein Data Bank in Europe (PDBe)
  33. RCSB Protein Data Bank (RCSB PDB)
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    https://www.rcsb.org/pages/policies
  34. Springer Nature
  35. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  36. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  37. Wikidata
  38. Wikipedia
  39. Wiley
  40. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  41. PubChem
  42. GHS Classification (UNECE)
  43. EPA Substance Registry Services
  44. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  45. PATENTSCOPE (WIPO)
CONTENTS