VALACYCLOVIR (Generic for VALTREX)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Valacyclovir may be administered without regard to meals.
Extemporaneous Compounding-Oral
Extemporaneous preparation of 25 mg/mL or 50 mg/mL valacyclovir oral suspension
-With a mortar and pestle, grind the required number of caplets into a fine powder (five 500 mg tablets for 25 mg/mL suspension or ten 500 mg tablets for 50 mg/mL suspension).
-Add 5 mL aliquots of Suspension Structured Vehicle USP-NF (SSV) to the powder until a paste is formed. All powder should be wetted.
-Continue to add 5 mL aliquots of SSV until a concentrated suspension is formed. A minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV should be used to form the concentrated suspension.
-Transfer the suspension to a 100 mL flask.
-In the mortar, dissolve cherry flavor in approximately 5 mL SSV. Follow the instructions provided by the cherry flavor manufacturer to determine the amount of cherry flavor that should be added to the 5 mL SSV.
-Transfer the cherry flavor mixture to the flask.
-Rinse the mortar at least 3 times with 5 mL aliquots of SSV, transferring the rinsing to the flask between additions.
-Add additional SSV to the flask to make a total volume of 100 mL.
-Transfer the suspension to an amber glass bottle.
-Shake well before each use.
-Storage: The oral suspension is stable for 28 days when stored under refrigeration (2 to 8 degrees C, 36 to 46 degrees F).

The safety profile of valacyclovir that is included in the FDA-approved product label is based on data from 177 pediatric patients ages 1 month to 17 years. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.

Nausea (8%) and diarrhea (5%) were the most frequent gastrointestinal adverse effects reported in pediatric patients receiving valacyclovir during clinical trials. Vomiting (3% to 6%) and abdominal pain (3% to 11%) have also been reported in adult patients receiving valacyclovir in clinical trials.

Cases of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have occurred in patients with advanced HIV disease and bone marrow and renal transplant recipients receiving valacyclovir (8 grams per day) during adult clinical trials. Some of these cases were associated with fatal outcomes. Discontinue valacyclovir treatment immediately if clinical symptoms and laboratory findings suggest development of TTP or HUS. Other hematologic abnormalities observed in adult clinical trials with valacyclovir include anemia (less than 1%), leukopenia (1% or less), decreased neutrophil counts/neutropenia (18%), and thrombocytopenia (0.1% to 3%). Aplastic anemia and leukocytoclastic vasculitis have also been observed in postmarketing reports.

Headache (17%) was the most commonly reported adverse event in pediatric patients receiving valacyclovir during clinical trials. Depression (5% to 7%) and dizziness (2% to 4%) were reported in adult clinical trials. Other central nervous system adverse events, including agitation, hallucinations, confusion, delirium, encephalopathy, and seizures, have been reported during treatment with valacyclovir. These adverse reactions are more likely to occur in elderly patients; however, they have been reported in both adult and pediatric populations. Other adverse events noted in postmarketing reports include aggressive behavior, ataxia, coma, decreased consciousness, dysarthria, tremor, mania, psychosis, and visual impairment. Discontinue valacyclovir treatment if central nervous system adverse reactions occur.

Cases of renal failure (unspecified) have been reported during treatment with valacyclovir. Patient populations at increased risk of developing valacyclovir-associated renal failure include patients with underlying renal disease who receive dosages not adjusted based on their renal function, patients concurrently receiving other nephrotoxic medications, and patients without adequate hydration. Dehydration has been reported as an adverse effect of valacyclovir in pediatric patients; monitor hydration status carefully. Increases in serum creatinine (more than 1.5-times the upper limit of normal) were reported in up to 0.7% of adult patients in clinical trials. If anuria or renal failure develops during treatment with valacyclovir, the patient may benefit from hemodialysis until restoration of renal function can be achieved. Renal pain that may be associated with renal failure has also been observed in postmarketing reports.

Elevated hepatic enzymes (1% to 16%) and alkaline phosphatase (4%) were reported in adult patients receiving valacyclovir during clinical trials. Hepatitis has been reported with valacyclovir in postmarketing experience.

Rhinorrhea was reported in 2% of pediatric patients receiving valacyclovir during clinical trials. Pharyngitis (16%, reported as nasopharyngitis) and upper respiratory tract infection (9%) were reported in adult clinical trials.

Fever (4%) and dehydration (2%) were reported in pediatric patients receiving valacyclovir during clinical trials. Other general adverse reactions reported during adult clinical trials include arthralgia (5% to 6%), fatigue (8%), and dysmenorrhea (5% to 8%).

Although not reported in pediatric patients, rash was reported in 8% of adult patients receiving valacyclovir during clinical trials. Acute hypersensitivity reactions, including anaphylactoid reactions, anaphylaxis, angioedema, dyspnea, facial edema, pruritus, rash, and urticaria, have been reported with valacyclovir during postmarketing experience. Other dermatologic adverse events noted in postmarketing reports include alopecia, erythema multiforme, and photosensitivity rash.

Sinus tachycardia and hypertension were noted in valacyclovir postmarketing reports.

Valacyclovir is contraindicated in patients with acyclovir hypersensitivity or valacyclovir hypersensitivity.

Use valacyclovir with caution in patients with renal impairment or renal failure; dosage adjustments are required in patients with a CrCl less than 50 mL/minute/1.73 m2. Acute renal failure and CNS toxicity have been reported in patients with underlying renal dysfunction who have received inappropriately high doses of valacyclovir for their level of renal function. Patients receiving potentially nephrotoxic drugs together with valacyclovir may have an increased risk of renal dysfunction.

Maintain adequate hydration in all patients receiving valacyclovir. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Cases of acute renal failure have been observed in patients with dehydration.

Description: Valacyclovir is a prodrug that is rapidly converted to acyclovir in vivo. The result of administering valacyclovir, the L-valyl ester of acyclovir, is significantly improved oral bioavailability, which allows for less frequent dosing compared to oral acyclovir. Valacyclovir is approved for the treatment of chickenpox and herpes labialis (cold sores) in pediatric patients; however, it has been used off-label for herpes zoster and other herpes simplex infections. Valacyclovir is FDA-approved in pediatric patients as young as 2 years of age.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: B virus (cercopithecine herpesvirus), cytomegalovirus (CMV), Epstein-Barr virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of herpes simplex virus infection, including herpes labialis and herpes genitalis*:
-for the treatment of herpes labialis in immunocompetent patients:
Oral dosage:
Children and Adolescents 12 to 17 years: 2 g PO every 12 hours for 1 day at the first sign or symptom of a cold sore. Efficacy has not been established when treatment is initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer).
-for the treatment of herpes labialis in persons living with HIV*:
Oral dosage:
Adolescents: 1 g PO every 12 hours for 5 to 10 days. Efficacy has not been established when treatment is initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer).
-for the treatment of initial episode of herpes genitalis in immunocompetent patients*:
Oral dosage:
Infants and Children weighing less than 45 kg: 40 mg/kg/day PO divided twice daily for 7 to 10 days. Treatment is most effective if started within 48 hours of the onset of signs or symptoms. Efficacy has not been established when treatment is initiated more than 72 hours after the onset of signs and symptoms.
Children weighing 45 kg or more and Adolescents: 1 g PO every 12 hours for 7 to 10 days or until clinical resolution. Treatment is most effective if started within 48 hours of the onset of signs or symptoms. Efficacy has not been established when treatment is initiated more than 72 hours after the onset of signs and symptoms.
-for the treatment of initial episode of herpes genitalis in persons living with HIV*:
Oral dosage:
Adolescents: 1 g PO every 12 hours for 7 to 10 days or until clinical resolution. Treatment is most effective if started within 48 hours of the onset of signs or symptoms. Efficacy has not been established when treatment is initiated more than 72 hours after the onset of signs and symptoms.
-for the treatment of recurrent herpes genitalis in immunocompetent patients*:
Oral dosage:
Children weighing 45 kg or more and Adolescents: 500 mg PO every 12 hours for 3 days or 1 g PO once daily for 5 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 24 hours after the onset of symptoms.
-for the treatment of recurrent herpes genitalis in persons living with HIV*:
Oral dosage:
Adolescents: 1 g PO every 12 hours for 5 to 10 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 24 hours after the onset of symptoms.

For herpes genitalis prophylaxis* or secondary genital herpes simplex infection prophylaxis* (i.e., long-term suppressive therapy*) in patients with frequent or severe recurrences:
-for long-term suppressive therapy of recurrent herpes genitalis in immunocompetent patients:
Oral dosage:
Children weighing 45 kg or more and Adolescents: 1 g or 500 mg PO once daily; the 500 mg/day regimen may be less effective in patients who have very frequent recurrences (i.e., 10 or more episodes/year).
-for long-term suppressive therapy of recurrent herpes genitalis in persons living with HIV:
Oral dosage:
Adolescents: 500 mg PO twice daily. Although safety and efficacy beyond 6 months have not been established, guidelines suggest suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually.

For the treatment of varicella (chickenpox) infection:
-for the treatment of varicella (chickenpox) infection in immunocompetent patients:
Oral dosage:
Children and Adolescents 2 to 17 years: 20 mg/kg/dose (Max: 1 g/dose) PO 3 times daily for 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
-for the treatment of uncomplicated varicella (chickenpox) infection in immunocompromised patients*:
Oral dosage:
Children 2 to 12 years: 20 mg/kg/dose (Max: 1 g/dose) PO 3 times daily for 7 to 10 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
Adolescents: 1 g PO 3 times daily for 5 to 7 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
-for the treatment of severe or complicated varicella (chickenpox) infection* in immunocompromised patients as stepdown therapy from IV acyclovir:
Oral dosage:
Adolescents: 1 g PO 3 times daily for a total treatment course of 7 to 10 days.

For the treatment of herpes zoster (shingles) infection*:
-for the treatment of herpes zoster (shingles) infection in immunocompetent patients:
Oral dosage:
Adolescents: 1 g PO 3 times daily for 7 days. Initiate therapy at first sign or symptom; therapy is the most effective if initiated within 48 hours of rash onset. Efficacy of treatment initiation after 72 hours of sign/symptom onset has not been established.
-for the treatment of herpes zoster (shingles) infection in persons living with HIV:
Oral dosage:
Adolescents: 1 g PO 3 times daily for 7 to 10 days for localized infections; a longer duration of therapy may be required if lesions are slow to resolve. For those with extensive cutaneous lesions or visceral involvement, use as stepdown therapy after IV acyclovir to complete a 10- to 14-day course.

For the treatment of acute retinal necrosis (ARN)* due to varicella-zoster virus in persons living with HIV:
Oral dosage:
Children 2 to 12 years: 20 mg/kg/dose (Max: 1 g/dose) PO 3 times daily for 4 to 6 weeks after initial IV acyclovir therapy.
Adolescents: 1 g PO 3 times daily for at least 14 weeks after initial therapy with intravenous acyclovir and intravitreal ganciclovir.

For post-exposure varicella (chickenpox) infection prophylaxis* in immunocompromised patients:
Oral dosage:
Children 2 to 12 years: 20 mg/kg/dose PO 3 times daily (Max: 1 g/dose) for 7 days, beginning 7 to 10 days after exposure, is recommended by some experts when passive immunization with varicella-zoster immune globulin is not feasible. Due to the lack of data of valacyclovir/acyclovir prophylaxis in persons with HIV, other experts consider it prudent to wait until the rash appears to begin treatment. Post-exposure prophylaxis is indicated for patients who lack evidence of immunity to varicella with substantial exposure to a contact with varicella or herpes zoster. Some limit this recommendation to children who are severely immunocompromised (i.e., CDC Immunologic Category 3), particularly if also classified as CDC Clinical Category C and experiencing high HIV RNA plasma viral load.
Adolescents: 1 g PO 3 times daily for 5 to 7 days beginning 7 to 10 days after exposure may be considered as an alternative to varicella-zoster immune globulin; however, this intervention has not been studied in persons with HIV.

For the treatment of herpes zoster ocular infection* (herpes zoster ophthalmicus), including viral conjunctivitis*:
-for the treatment of herpes zoster ocular infection in immunocompetent persons*:
Oral dosage:
Children and Adolescents 12 to 17 years: 1 g PO every 8 hours for 7 days. Initiate therapy within 48 to 72 hours of rash onset.
-for the treatment of herpes zoster ocular infection in immunocompromised persons*:
NOTE: Oral therapy can be considered for those who are not severely immunosuppressed.
Oral dosage:
Children and Adolescents 12 to 17 years: 1 g PO 3 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 year: Safety and efficacy have not been established.
2 to 11 years: 60 mg/kg/day (Max: 3 g/day) PO.
12 years: 4 g/day PO for one-day treatment regimens or 3 g/day PO for regimens lasting longer than 1 day.
-Adolescents
4 g/day PO for one-day treatment regimens or 3 g/day PO for regimens lasting longer than 1 day.

Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary.

Patients with Renal Impairment Dosing
Pediatric dosage adjustment recommendations based on a usual dosage of 20 mg/kg per dose PO every 8 hours (Max: 3 g/day)
GFR 50 mL/minute/1.73 m2 or more: No dosage adjustment needed.
GFR 30 to 49 mL/minute/1.73 m2: 20 mg/kg per dose PO every 12 hours.
GFR 10 to 29 mL/minute/1.73 m2: 20 mg/kg per dose PO every 24 hours.
GFR less than 10 mL/minute/1.73 m2: 10 mg/kg per dose PO every 24 hours.

FDA-labeled dosage adjustments in adults
CrCl 50 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 49 mL/minute: For regimens of 1 g PO every 8 hours, reduce dose to 1 g PO every 12 hours. For one-day treatment of herpes labialis (usually 2 g PO every 12 hours for 2 doses), give 1 g PO every 12 hours for 2 doses. Other regimens do not require a dosage adjustment.
CrCl 10 to 29 mL/minute: For regimens of 1 g PO every 8 to 12 hours, reduce dose to 1 g PO every 24 hours. For regimens of 1 g PO once daily or 500 mg PO every 12 hours, reduce dose to 500 mg PO once daily. For regimens of 500 mg PO once daily, change dose to 500 mg PO every 48 hours. For one-day treatment of herpes labialis (usually 2 g PO every 12 hours for 2 doses), give 500 mg PO every 12 hours for 2 doses.
CrCl less than 10 mL/minute: For regimens of 1 g PO every 8 to 24 hours or 500 mg PO every 12 hours, reduce dose to 500 mg PO once daily. For regimens of 500 mg PO once daily, change dose to 500 mg PO every 48 hours. For one-day treatment of herpes labialis (usually 2 g PO every 12 hours for 2 doses), give 500 mg PO for 1 dose.

Intermittent hemodialysis
The FDA-approved product label recommends administering the usually recommended dose after hemodialysis. Alternatively, 10 mg/kg per dose PO every 24 hours after dialysis (based on a usual dosage of 20 mg/kg per dose PO every 8 hours) has been recommended.

Peritoneal dialysis
FDA-approved product label suggests that supplemental doses of valacyclovir should not be required after chronic ambulatory peritoneal dialysis; however, the effects of peritoneal dialysis on valacyclovir pharmacokinetics have not been studied. Dosing recommendations are based on the known effects of peritoneal dialysis on acyclovir pharmacokinetics. Other guidelines suggest 10 mg/kg per dose PO every 24 hours (based on a usual dosage of 20 mg/kg per dose PO every 8 hours).

Continuous renal replacement therapy (CRRT)
FDA-approved labeling suggests that supplemental doses of valacyclovir should not be required with continuous arteriovenous hemofiltration/dialysis (CAVHD). However, the effects of CAVHD on valacyclovir pharmacokinetics have not been studied. Dosing recommendations are based on the known effects of CAVHD on acyclovir pharmacokinetics. Other guidelines suggest not administering valacyclovir during CRRT and switching to an intravenously administered agent.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: 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 monophosphate by viral thymidine kinase (TK), then to diphosphate by cellular guanylate kinase, and finally to 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: Valacyclovir is administered orally. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Valacyclovir is 14% to 18% bound to plasma proteins, and acyclovir is 9% to 33% protein-bound. 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 concentrations 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. In general, the pharmacokinetics of acyclovir in pediatric patients greater than 1 year of age are similar to those of adults.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Valacyclovir is rapidly absorbed after 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 that valacyclovir may saturate absorption sites along the GI tract. In adult patients receiving valacyclovir doses ranging from 250 mg to 1,000 mg, there was a less than dose-proportional increase in acyclovir maximum concentration and AUC after single-dose and multiple-dose administration. 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
Pediatrics
Infants
In a clinical trial of infants 1 to 2 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.

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 1.5 to 2.5 hours. The adult half-life generally ranges from 2.5 to 3.3 hours.

Hepatic Impairment
The rate, but not the extent 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 from 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. 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.

Other
HIV Infection
The pharmacokinetics of valacyclovir were not significantly different in persons with HIV compared with healthy volunteers.