Description of ValacyclovirÂ
Valacyclovir is an antiviral agent with activity against alpha-herpes viruses. It is FDA approved for the treatment of: herpes labialis (cold sores) in patients 12 years and older; chickenpox in pediatric patients aged 2 to less than 18 years; herpes zoster (shingles) in immunocompetent adults; and genital herpes (initial episode, recurrent episodes, suppressive therapy, and reduction of transmission) in immunocompetent adults. Valacyclovir is the L-valyl ester of acyclovir; the result of an effort to develop a prodrug to improve acyclovir oral bioavailability. Improved bioavailability means less frequent dosing for valacyclovir than acyclovir, which is especially beneficial during maintenance therapy. While valacyclovir is only available as an oral tablet, extemporaneous compounding instructions are available to prepare an oral suspension.
Mechanism of Action of ValacyclovirÂ
Valacyclovir is rapidly converted to acyclovir, which inhibits DNA synthesis. Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). Acyclovir inhibits viral DNA synthesis and must be phosphorylated intracellularly to be active. Acyclovir is converted to the monophosphate by viral thymidine kinase (TK), then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Acyclovir triphosphate stops replication of herpes viral DNA by the following 3 mechanisms: competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.
Herpes virus DNA polymerases differ in sensitivity to acyclovir. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral thymidine kinase. Acyclovir is effective only against actively replicating viruses; therefore, it does not eliminate the latent herpes virus genome. Uninfected cells show only minimal phosphorylation of acyclovir, and there is only a small amount of acyclovir taken up into these cells. The concentration of acyclovir triphosphate is 40- to 100- times higher in HSV-infected cells than non-infected cells. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.
Viral resistance to acyclovir may occur due to loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA-polymerase sensitivity. The alterations in these enzymes occur due to point mutations or base insertions or deletions in the specific genes. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents activated by thymidine kinase (e.g., foscarnet, famciclovir, and penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in immunocompromised patients. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.
Pharmacokinetics of Valacyclovir
Valacyclovir is administered orally. It binds to plasma protein in the range 13.5 to 17.9%. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. The binding of acyclovir to plasma protein ranges from 9 to 33%. Acyclovir undergoes some metabolism by aldehyde oxidase, alcohol dehydrogenase, and aldehyde dehydrogenase to produce inactive metabolites. Microsomal hepatic enzymes do not contribute to the metabolism of valacyclovir or acyclovir. Plasma concentrations of valacyclovir are low and transient and become undetectable after 3 hours. Peak valacyclovir plasma levels are generally less than 0.5 mcg/mL at all dosage levels. Acyclovir is eliminated primarily by the kidneys. Plasma elimination half-life of acyclovir is between 2.5 and 3.3 hours in patients with normal renal function.
Route-Specific Pharmacokinetics
Oral Route
Valacyclovir is rapidly absorbed following oral administration. Absorption is unaffected by administration with food. In healthy volunteers, relative bioavailability of valacyclovir compared to that of acyclovir was 3.3 to 5 times greater; acyclovir bioavailability is 54% when administered as valacyclovir compared to 10 to 20% when administered as acyclovir itself. It has been suggested valacyclovir may saturate absorption sites along the GI tract. Although repeat dosing does not reduce acyclovir concentrations, the Cmax and AUC for acyclovir are not dose-proportional. Valacyclovir in doses of 1 to 2 g PO four times daily yields plasma acyclovir concentrations and AUC levels similar to that obtained after IV administration of acyclovir 5 to 10 mg/kg every 8 hours. As a result of improved oral bioavailability, valacyclovir requires less frequent dosing than acyclovir.
Special Populations
Hepatic Impairment
The rate but not the extend of conversion of valacyclovir to acyclovir is reduced in patients with moderate or severe (with and without ascites) hepatic disease; however, the acyclovir half-life is not affected.
Renal Impairment
In patients with end-stage renal disease, the average half-life of acyclovir is increased to about 14 hours.
Dialysis
During hemodialysis, acyclovir half-life is about 4 hours. Hemodialysis removes about one third of acyclovir in the body during a 4-hour session. Plasma clearance of acyclovir in dialysis patients is about 86 mL/min/1.73 m2, compared to 679 mL/min/1.73 m2 in healthy volunteers. Patients with reduced creatinine clearance require dosage reduction. The removal of acyclovir after arteriovenous hemofiltration/dialysis (CAVHD) or ambulatory peritoneal dialysis (CAPD) is less pronounced than with hemodialysis, and pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease not receiving dialysis. Supplemental doses of valacyclovir are not required following CAVHD or CAPD.
Pediatrics
Children and Adolescents
Acyclovir clearance is faster in infants and then slows during early childhood to approach adult values. In clinical trials of oral valacyclovir, the mean acyclovir half-life in children and adolescents ranged from 1.46 to 2.51 hours. The adult half-life generally ranges from 2.5 to 3.3 hours.
Infants
In a clinical trial of infants aged 1 to less than 3 months, a single dose of valacyclovir 25 mg/kg produced higher acyclovir exposures (Cmax: 30% higher, AUC: 60% higher) than acyclovir exposures after a 1 g dose of valacyclovir given to adults.
Generic Name
Valacyclovir Hydrochloride
Brand Names
Valtrex
Therapeutic Class
Antiviral
Guanosine Nucleoside Analog
Viral DNA Polymerase Inhibitor
FDA-Label Indications
Genital herpes simplex, Initial and recurrent episodes: Adult
Herpes labialis: Adult
Herpes labialis: Pediatric: yes (12 years or older)
Herpes zoster, Shingles: Adult
HIV infection – Recurrent genital herpes simplex, Suppression: Adult
Recurrent genital herpes simplex, Suppression and transmission reduction: Adult
Varicella: Pediatric: yes (2 years or older)
Common Effects
Dermatologic: Rash (8% )
Gastrointestinal: Abdominal pain (1% to 11% ), Nausea (5% to 15% ), Vomiting (less than 1% to 6% )
Neurologic: Headache (13% to 38% )
Other: Fatigue (8% )
Serious Effects
Hematologic: Thrombotic thrombocytopenic purpura
Neurologic: Aseptic meningitis, Encephalopathy, Seizure
Renal: Hemolytic uremic syndrome
Administration
Oral: Take with or without food
How Supplied – Trade
ValACYclovir HCl AvPak: Oral Tablet: 1 GM, 500 MG
Valtrex: Oral Tablet: 1 GM, 500 MG
How Supplied – Generic
Oral Tablet: 1 GM, 500 MG
Adult Dose
Acute retinal necrosis: (HIV-infected) Acyclovir 10 to 15 mg/kg IV every 8 hours for 10 to 14 days, followed by valacyclovir 1 g orally 3 times daily for 6 weeks plus ganciclovir 2 mg/0.05 mL intravitreally twice weekly for 1 to 2 doses (guideline dosage)
Bell’s palsy; Adjunct: 1000 mg ORALLY 3 times daily for 7 days plus steroid therapy (off-label dosage)
Genital herpes simplex, Initial and recurrent episodes: Initial episode: 1 g orally twice daily for 10 days; most effective when started within 48 hours of signs and symptoms
Genital herpes simplex, Initial and recurrent episodes: Recurrent episode: 500 mg orally twice daily for 3 days; start within 24 hours of onset of signs and symptoms (FDA dosage) ,
Genital herpes simplex, Initial and recurrent episodes: Recurrent episode: 1 g once daily for 5 days OR 500 mg orally twice daily for 3 days; initiate treatment preferably within 1 day of lesion onset or during preceding prodrome (guideline dosage)
Genital herpes simplex, Initial and recurrent episodes – HIV infection: 1 g orally twice daily for 5 to 14 days (guideline dosage)
Herpes labialis: 2 g ORALLY twice daily for 1 day; separate doses by 12 hours; start at the earliest onset of symptoms
Herpes labialis – HIV infection: 1 g orally twice daily for 5 to 10 days (guideline dosage)
Herpes labialis – HIV infection: (Chronic suppressive therapy) 500 mg orally twice daily (guideline dosage)
Herpes zoster, Shingles: 1 g ORALLY 3 times daily for 7 days; start within 48 hours of rash onset
Herpes zoster, Shingles – HIV infection: (Acute localized dermatomal) 1 g orally 3 times daily for 7 to 10 days; may treat longer if lesions are slow to resolve (guideline dosage)
Herpes zoster, Shingles – HIV infection: (Extensive cutaneous or visceral involvement, HIV-infected) Acyclovir 10 to 15 mg/kg IV every 8 hours until clinical improvement, then switch to valacyclovir 1 g orally 3 times daily for a total duration of 10 to 14 days (guideline dosage)
HIV infection – Recurrent genital herpes simplex, Suppression: 500 mg orally twice daily (FDA and guideline dosage)
HIV infection – Varicella: (Uncomplicated cases) 1 g orally 3 times daily for 5 to 7 days (guideline dosage)
Recurrent genital herpes simplex, Suppression and transmission reduction: Suppressive therapy, 1 g orally once daily; may consider 500 mg orally once daily for patients with 9 or fewer recurrences/year
Recurrent genital herpes simplex, Suppression and transmission reduction: Reduction of transmission, 9 or fewer recurrences/year: 500 mg orally once daily
Pediatric Dose
Herpes labialis: (12 years or older) 2 g ORALLY twice daily for 1 day; separate doses by 12 hours; start at the earliest onset of symptoms
Varicella: (2 years or older) 20 mg/kg ORALLY 3 times daily for 5 days; MAX dose 1 g 3 times daily; begin within 24 hours after rash onset