Valaciclovir

J05A - Direct acting antivirals ATC J05AB11 Small molecule approved 1995 Oral Prodrug Natural product

Active form: Acyclovir Triphosphate.

JFDA label: Valtrex Tablets

Mechanism of Action

Valacyclovir is rapidly and nearly completely converted to acyclovir by intestinal and hepatic metabolism. Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Indications

Off-label

B virus, postexposure prophylaxis
CMV reactivation (prevention in allogeneic HSCT recipients)
HSV keratitis
HSV reactivation (prevention in seropositive HSCT recipients)
HSV, orolabial (cold sores) infection in HIV-infected patients (adolescents and adults)
Herpes simplex virus (HSV), genital infection in HIV-infected patients (adolescents and adults)
Herpes zoster (shingles) in HIV-infected patients (adolescents and adults)
VZV reactivation (prevention in HSCT recipients)
VZV, postexposure prophylaxis (HSCT recipients)
Varicella infection (chickenpox) in HIV-infected patients (adolescents and adults)
Varicella zoster virus (VZV) acute retinal necrosis (ARN) in HIV-infected patients (adolescent and adults)

Contraindications

Source: Lexicomp

Hypersensitivity to valacyclovir, acyclovir, or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (6)

Very Common Headache

Common depression · dizziness · Fatigue · Headache

Uncommon CNS effects (high-dose — confusion, hallucinations)

Hepatobiliary disorders (3)

Very Common increased serum ALT · Increased serum AST

Common Increased serum alkaline phosphatase

Blood and lymphatic system disorders (3)

Common leukopenia · Thrombocytopenia

Very Rare Thrombotic thrombocytopaenic purpura / haemolytic uraemic syndrome (high-dose, immunocompromised)

Metabolism and nutrition disorders (1)

Common Dehydration

Gastrointestinal disorders (5)

Very Common abdominal pain · Nausea

Common diarrhea · Nausea · Vomiting

Skin and subcutaneous tissue disorders (1)

Common Skin rash

Musculoskeletal and connective tissue disorders (1)

Common Arthralgia

Infections and infestations (1)

Common Herpes simplex infection

General disorders and administration site conditions (1)

Common Fever

Respiratory, thoracic and mediastinal disorders (2)

Very Common Nasopharyngitis

Common Rhinorrhea

Dosing

Source: Lexicomp

Herpes labialis (cold sores): Oral: 2 g every 12 hours for 1 day Herpes labialis (cold sores) in HIV-infected patients (off-label use): Oral: 1 g twice daily for 5 to 10 days (HHS [OI adult 2016]) Herpes zoster (shingles): Oral: Immunocompetent patients: 1 g 3 times daily for 7 days HIV-infected patients, acute localized dermatomal (off-label use): 1 g 3 times daily for 7 to 10 days; consider longer duration if lesions resolve slowly (HHS [OI adult 2016]) Herpes simplex virus (HSV), genital infection: Oral: Manufacturer’s labeling: Initial episode: Immunocompetent patients: 1 g twice daily for 10 days. Note: CDC STD guidelines recommend a treatment duration of 7 to 10 days (CDC [Workowski 2015]). Recurrent episode: Immunocompetent patients: 500 mg twice daily for 3 days or alternatively (off-label dose), 1,000 mg once daily for 5 days (CDC [Workowski 2015]) Reduction of transmission: 500 mg once daily (source partner) Suppressive therapy: Immunocompetent patients: 1 g once daily (500 mg once daily in patients with ≤9 recurrences per year). Note: Safety and efficacy have been documented for up to 1 year (CDC [Workowski 2015]). HIV-infected patients (CD4 ≥100 cells/mm3): 500 mg twice daily Alternate dosing: HIV-infected patients: Initial or recurrent episodes (off-label use): 1 g twice daily for 5 to 10 days (HHS [OI adult 2016]) Chronic suppressive therapy: 500 mg twice daily; continue indefinitely regardless of CD4 count in patients with severe recurrences or in patients who want to minimize frequency of recurrences (HHS [OI adult 2016]) B virus, postexposure prophylaxis (off-label use): Oral: 1 g 3 times daily for 14 days (Tunkel 2008) CMV reactivation (prevention in allogeneic HSCT recipients) (off-label use): Oral: 2 g 3 to 4 times daily; in combination with screening for CMV reactivation; begin at engraftment and continue to day 100 (Tomblyn 2009) HSV keratitis (off-label use) (White 2014): Oral Epithelial keratitis, dendritic: 500 mg twice daily for 7 to 10 days Epithelial keratitis, geographic: 1 g 3 times daily for 14 to 21 days Stromal keratitis, without epithelial ulceration: 500 mg once daily; use in combination with therapeutic dose of topical corticosteroid, for the duration of corticosteroid treatment Stromal keratitis, with epithelial ulceration: 1 g 3 times daily for 7 to 10 days, then reduce to 500 mg once daily; use in combination with therapeutic dose of topical corticosteroid, for the duration of corticosteroid treatment Endothelial keratitis: 500 mg twice daily for 7 to 10 days, then reduce to 500 mg once daily; use in combination with therapeutic dose of topical corticosteroid, for the duration of corticosteroid treatment. HSV reactivation (prevention in seropositive HSCT recipients) (off-label use) (Tomblyn 2009): Oral: Early reactivation: 500 mg once daily or 500 mg twice daily in highly immune-suppressed patients (eg, T cell depletion, anti-T cell antibodies, high-dose steroids). Initiate at the beginning of conditioning t

(For additional information see "Valacyclovir: Pediatric drug information") Herpes labialis (cold sores): Children ≥12 years and Adolescents: Oral: Refer to adult dosing. Herpes labialis (cold sores) in HIV-infected patients (off-label use): Adolescents: Oral: Refer to adult dosing. Herpes simplex virus, genital infection in HIV-infected patients: Adolescents (off-label population): Oral: Initial or recurrent episodes (off-label use): 1 g twice daily for 5 to 14 days (HHS [OI adult 2015]) Chronic suppressive therapy (off-label dose): 500 mg twice daily; continue indefinitely regardless of CD4 count in patients with severe recurrences or in patients who want to minimize frequency of recurrences (HHS [OI adult 2015]) Herpes zoster (shingles) in HIV-infected patients (off-label use): Adolescents: Oral: Refer to adult dosing. Varicella (chickenpox): Immunocompetent patients: Children ≥2 years and Adolescents: Oral: 20 mg/kg/dose 3 times daily for 5 days (maximum: 1 g 3 times daily) HIV-infected patients (off-label use): Adolescents: Oral: Refer to adult dosing.

Refer to adult dosing.

Herpes zoster: Adults: CrCl 30 to 49 mL/minute: 1 g every 12 hours CrCl 10 to 29 mL/minute: 1 g every 24 hours CrCl Genital herpes: Adults: US labeling: Initial episode: CrCl 10 to 29 mL/minute: 1 g every 24 hours CrCl Recurrent episode: CrCl Suppressive therapy: CrCl For usual dose of 1 g every 24 hours or 500 mg every 12 hours, decrease dose to 500 mg every 24 hours For usual dose of 500 mg every 24 hours, decrease dose to 500 mg every 48 hours Canadian labeling: Initial episode: CrCl 10 to 29 mL/minute: 1 g every 24 hours CrCl Recurrent episode: CrCl 10 to 29 mL/minute: 500 mg every 24 hours CrCl Suppressive therapy: CrCl 10 to 29 mL/minute: Immunocompetent or HIV-infected patients: 500 mg every 24 hours Immunocompetent patients with ≤9 recurrences/year: 500 mg every 48 hours CrCl Immunocompetent or HIV-infected patients: 500 mg every 24 hours Immunocompetent patients with ≤9 recurrences/year: 500 mg every 48 hours Herpes labialis (cold sores): Adolescents and Adults (US labeling) or Adults (Canadian labeling): CrCl 30 to 49 mL/minute: 1 g every 12 hours for 2 doses CrCl 10 to 29 mL/minute: 500 mg every 12 hours for 2 doses CrCl Hemodialysis: Dialyzable (~33% removed during 4-hour session); administer dose postdialysis Chronic ambulatory peritoneal dialysis/continuous arteriovenous hemofiltration dialysis: Pharmacokinetic parameters are similar to those in patients with ESRD; supplemental dose not needed following dialysis

No dosage adjustment necessary.

Warnings & Precautions

Source: Lexicomp

CNS effects

CNS adverse effects (including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy) have been reported in both adult and pediatric patients with or without renal dysfunction. Elderly patients are more likely to experience CNS adverse effects.

Thrombotic microangiopathy

Has occurred in immunocompromised patients (at doses of 8 g/day). Disease-related concerns:

Renal impairment

Use caution in patients with renal impairment, the elderly, and/or those receiving nephrotoxic agents. Acute renal failure and CNS effects have been observed in patients with renal dysfunction; dose adjustment may be required. Precipitation in renal tubules may occur; maintain adequate hydration. Special populations:

Elderly

Use with caution in the elderly; CNS effects have been reported.

Immunocompromised patients

Advanced HIV (CD4 3): Safety and efficacy have not been established for treatment/suppression of recurrent genital herpes or disseminated herpes in patients with profound immunosuppression. Other warnings/precautions:

Appropriate use

For cold sores, treatment should begin with earliest symptom (tingling, itching, burning). For genital herpes, treatment should begin as soon as possible after the first signs and symptoms (within 72 hours of onset of first diagnosis or within 24 hours of onset of recurrent episodes). For herpes zoster, treatment should begin within 72 hours of onset of rash. For chickenpox, treatment should begin with earliest sign or symptom.

Pregnancy & Lactation

Pregnancy

FDA category B

Safe

500 mg twice daily from 36 weeks for recurrent genital herpes to prevent neonatal herpes

Lactation

RID 5.1%

Valacyclovir is rapidly metabolized to acyclovir. Following administration of valacyclovir, acyclovir is present in breast milk; unchanged valacyclovir has not been detected in breast milk. Following administration of valacyclovir, the relative infant dose (RID) of acyclovir is 5.1% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of intravenous acyclovir of 30 mg/kg/day. In general, breastfeeding is considered acceptable wh

Monitoring

Clinical pearl	Urinalysis, BUN, serum creatinine, liver enzymes, and CBC

Chemistry & Properties

Formula	C13H20N6O4
Molecular weight	324.34 g/mol
IUPAC name	2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
CAS	124832-26-4
PubChem CID	135398742
InChIKey	`HDOVUKNUBWVHOX-QMMMGPOBSA-N`
logP	-0.8 (XLogP -0.9)
Polar surface area	151.14 Å²
H-bond acceptors / donors	9 / 3
Drug-likeness (QED)	0.44
Lipinski violations	0

SMILES

CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.983 h
Volume of distribution	1.349 L/kg
Protein binding	17.6%
BBB penetrant	Yes

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)P-gp (Inhibitor)PEPT2 (Inhibitor)P-gp (Substrate)PEPT1 (Substrate)PEPT2 (Substrate)

Drug–drug interactions (37, DDInter)

Interacting drug	Severity	Management
Diatrizoate	major
Everolimus	major
Iodipamide	major
Iodixanol	major
Iohexol	major
Iopamidol	major
Iopromide	major
Iothalamic acid	major
Ioversol	major
Ioxilan	major
Sirolimus	major
Tacrolimus	major
Temsirolimus	major
Amikacin	moderate
Amikacin (liposome)	moderate
Balsalazide	moderate
Carboplatin	moderate
Cisplatin	moderate
Cladribine	moderate
Clofarabine	moderate
Cyclosporine	moderate
Gentamicin	moderate
Iopodic acid	moderate
Mesalazine	moderate
Methotrexate	moderate
Neomycin	moderate
Olsalazine	moderate
Oxaliplatin	moderate
Paromomycin	moderate
Pemetrexed	moderate
Pentamidine	moderate
Streptomycin	moderate
Sulfasalazine	moderate
Talimogene laherparepvec	moderate
Trospium	moderate
Cimetidine	minor
Mycophenolic acid	minor

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Valtrex Tablets	Tablet 500 mg	10 tab pack varies	Suleiman Tannous & Sons Co. Ltd	9.410
Valtrex Tablets	Tablet 500 mg	42 tab pack varies	Suleiman Tannous & Sons Co. Ltd	36.770