VALACYCLOVIR (Generic for VALTREX)

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.

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

Route-Specific Administration

Oral Administration
-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 tablets into a fine powder (five 500 mg tablets for 25 mg/mL suspension, ten 500 mg tablet 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 adverse effect profile of valacyclovir is similar to that of acyclovir. The most commonly reported adverse events are headache (11% to 38%), nausea (4% to 15%), and abdominal pain (3% to 11%). Other less common adverse events include arthralgia (5% to 6%), depression (5% to 7%), dizziness (2% to 4%), dysmenorrhea (5% to 8%), fatigue (8%), pharyngitis (16%, reported as nasopharyngitis), upper respiratory tract infection (9%, e.g., sinusitis), and vomiting (3% to 6%).

During clinical trials with valacyclovir (8 grams per day for 8 to 84 weeks), cases of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have occurred in patients with advanced HIV disease, bone marrow transplantations, and renal transplantations. Some of these cases were associated with fatal outcomes. In other studies of healthy and HIV-infected patients, there have been no reports of TTP or HUS during use of valacyclovir for the treatment or suppression of genital herpes when using lower doses (3 grams per day or less) and shorter treatment durations. Postmarket reports of these serious reactions have also been received. The manufacturer recommends discontinuing valacyclovir treatment if clinical symptoms and laboratory finding suggest development of TTP or HUS.

During clinical trials with valacyclovir in pediatric patients aged 1 month to less than 12 years, 5% of patients experienced diarrhea. Diarrhea has also been reported by adult patients during postmarketing use of valacyclovir.

During three valacyclovir clinical trials, pediatric patients aged 1 month to less than 12 years experienced systemic adverse reactions not previously reported in the adult population including pyrexia or fever (4%), dehydration (2%), and rhinorrhea (2%).

Hematologic abnormalities have occurred following treatment with valacyclovir during clinical trials. Laboratory changes observed in recipients of valacyclovir include anemia (0.2% to 0.8%), elevated hepatic enzymes (1% to 16%), neutropenia (0.6% to 18%), and thrombocytopenia (0.1% to 3%).

Cases of renal failure (unspecified) have been reported during treatment with valacyclovir. According to the manufacturer, the following patient populations are at increased risk of developing valacyclovir-associated renal failure: elderly patients, 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. If anuria or renal failure develops during treatment with valacyclovir, the patient may benefit from hemodialysis until restoration of renal function can be achieved.

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. Health care providers are advised to discontinue valacyclovir treatment in any patient that develops signs or symptoms of central nervous system adverse reactions.

During a clinical trial evaluating the use of valacyclovir for suppression of recurrent genital herpes in HIV-infected patients, 8% of valacyclovir recipients developed a rash; only 1% of the study patients who received a placebo developed a rash. Rashes have also been reported by patients during postmarketing use of valacyclovir.

During clinical experience with the use of valacyclovir, other severe adverse reactions have been reported to the manufacturer. Allergic reactions have included anaphylactoid reactions, anaphylaxis, angioedema, dyspnea, erythema multiforme, facial edema, pruritus, and urticaria. Neuropsychiatric reactions have included aggressive behavior, ataxia, impaired cognition, tremor, coma, mania, and psychosis. Hepatic and gastrointestinal reactions have included liver enzyme abnormalities, hepatitis, and diarrhea. Renal reactions have included elevated serum creatinine, renal failure (unspecified), renal pain (possibly associated with renal failure). Other reactions have included leukocytoclastic vasculitis, aplastic anemia, alopecia, dysarthria, photosensitivity, visual impairment, hypertension, and sinus tachycardia. Due to the uncontrolled and voluntary nature of postmarketing reports, neither the frequency nor a definitive causal relationship to valacyclovir can be established.

Valacyclovir is contraindicated in patients with acyclovir hypersensitivity or valacyclovir hypersensitivity. Because of similar chemical structures and possible cross-sensitivity, valacyclovir should be used with caution in patients with famciclovir hypersensitivity, ganciclovir hypersensitivity, penciclovir hypersensitivity, or valganciclovir hypersensitivity. Alternative agents such as foscarnet or cidofovir may be suitable since they are not structurally related to these antivirals.

Valacyclovir should be used with caution in patients with renal dysfunction. Patients with renal impairment or renal failure may require dosage adjustment. 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.

In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in geriatric patients ( >= 65 years) compared with younger adults. Elderly patients are more likely to have impaired renal function and may require lower doses of valacyclovir. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, agitation, hallucinations, confusion, delirium, and encephalopathy were reported more frequently in elderly patients.

Precipitation of acyclovir in renal tubules may occur when the solubility is exceeded in the intratubular fluid. Patients should be well-hydrated to maintain a high urine volume and avoid dehydration during treatment with valacyclovir.

The safe use of valacyclovir in neonates, infants, and children less than 2 years old has not been established. Oral administration of the related drug acyclovir has been studied in infants and children.

Clinical data regarding the use of valacyclovir and its metabolite, acyclovir, in pregnant women have not identified a drug-associated risk of major birth defects. The Acyclovir and Valacyclovir Pregnancy Registries have documented outcomes for 1,246 infants and fetuses exposed in utero to acyclovir (756 first trimester exposures) and 111 infants and fetuses exposed in utero to valacyclovir (28 first trimester exposures). The occurrence of major birth defects during the first trimester for acyclovir and valacyclovir was 3.2% (95% CI: 2.0% to 5.0%) and 4.5% (95% CI: 0.24% to 24.9%), respectively. There are insufficient data on the use of valacyclovir regarding miscarriages or adverse maternal or fetal outcomes; however, there are known risks to the fetus associated with untreated herpes simplex virus (HSV) infections during pregnancy. According to the manufacturer, a primary herpes occurrence during the first trimester has been associated with neonatal chorioretinitis, microcephaly, and skin lesions. In rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth. The risk of neonatal HSV infection varies from 1% for infections acquired in early pregnancy to 30% to 50% for genital HSV infections acquired in the third trimester.

There are no data on the effects of valacyclovir or its active metabolite, acyclovir, on a breast-fed infant or on milk production. Although the American Academy of Pediatrics (AAP) has not specifically evaluated valacyclovir, systemic maternal acyclovir is considered to be usually compatible with breast-feeding. In a small study of 5 lactating women, valacyclovir was administered orally as a single 500 mg dose. Peak acyclovir concentrations in breast milk ranged from 0.5- to 2.3-times (median 1.4) the corresponding maternal acyclovir serum concentrations, and the acyclovir AUC in breast milk ranged from 1.4- to 2.6-times (median 2.2) maternal serum AUC. Administration of valacyclovir 500 mg twice daily to a breast-feeding woman would provide the nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day, resulting in less than 1% of the exposure obtained after administering a neonatal intravenous dose for the treatment of neonatal herpes (i.e., 60 mg/kg/day). In the study, unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

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 acute retinal necrosis (ARN)* due to varicella-zoster virus in persons living with HIV:
Oral dosage:
Adults: 1 g PO 3 times daily for at least 14 weeks after initial therapy with intravenous acyclovir and intravitreal ganciclovir.
Adolescents: 1 g PO 3 times daily for at least 14 weeks after initial therapy with intravenous acyclovir and intravitreal ganciclovir.
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.

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:
Adults: 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).
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:
Adults: 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).
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:
Adults: 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.
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.
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.
-for the treatment of initial episode of herpes genitalis in persons living with HIV*:
Oral dosage:
Adults: 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.
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:
Adults: 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.
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:
Adults: 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.
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:
Adults: 1 g PO once daily. The dose may be reduced to 500 mg PO once daily for patients with a history of 9 or fewer recurrences per year. The 500 mg once daily regimen appears to be less effective than other regimens in patients with 10 or more episodes per year. Safety and efficacy beyond 1 year have not been established.
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:
Adults: 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.
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 reduction of transmission of genital herpes to an immunocompetent uninfected sex partner in immunocompetent patients with a history of 9 or fewer recurrences per year:
Oral dosage:
Adults: 500 mg PO once daily for the source partner in conjunction with safer sex practices. Use decreases risk of transmission to the uninfected partner in monogamous, heterosexual relationships when combined with safer sex practices. The efficacy of reducing transmission beyond 8 months in discordant couples has not been established.

For primary cytomegalovirus (CMV) disease prophylaxis*:
-for primary cytomegalovirus (CMV) disease prophylaxis* in patients after bone marrow transplantation:
Oral dosage:
Adults: Guidelines recommend 1 g PO four times daily as an option; however, this must be combined with monitoring and the use of preemptive therapy when necessary. 2 g PO four times daily was found to be as effective as IV ganciclovir in preventing CMV disease and potentially more effective than oral acyclovir.
-for primary cytomegalovirus (CMV) disease prophylaxis* in patients after kidney transplantation:
Oral dosage:
Adults: 2 g PO four times daily for 3 to 6 months as a prophylaxis option. In a randomized trial, 2 g PO four times a day for 90 days post-transplant significantly reduced the incidence of CMV disease in both CMV-seronegative and -seropositive patients. In this study, treatment with valacyclovir was associated with a decreased rate of CMV viremia and viruria, herpes simplex virus disease, and acute graft rejection. Additional studies suggest that valacyclovir may be as effective as oral ganciclovir.
-for primary cytomegalovirus (CMV) disease prophylaxis* in patients after heart transplantation:
Oral dosage:
Adults: Not recommended as an option by guidelines. A dose of 2 g PO four times a day (n = 14) was studied in a randomized, placebo-controlled trial. Prophylaxis was initiated within 72 hours after transplant and continued to day 90. Time to antigenemia was significantly prolonged in patients receiving valacyclovir. Significantly fewer valacyclovir patients developed CMV infection (45% vs. 92% placebo; p less than 0.05) during the 90-day treatment period, or required preemptive ganciclovir treatment. By the end of the six month trial period, virtually all patients in both groups (93% valacyclovir, 92% placebo) had evidence of CMV infection; however, the differences between treatment groups in the rates of CMV syndrome (14% vs. 46%; p = NS) and disease (7% vs. 31%; p = NS) were maintained.

For the treatment of herpes zoster (shingles) infection:
NOTE: Valacyclovir is not approved for the treatment of disseminated herpes zoster infections.
-for the treatment of herpes zoster (shingles) infection in immunocompetent patients:
Oral dosage:
Adults: 1 g PO 3 times daily for 7 days. Initiate therapy at first sign or symptom; therapy is 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.
Adolescents*: 1 g PO 3 times daily for 7 days. Initiate therapy at first sign or symptom; therapy is 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:
Adults: 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.
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 varicella (chickenpox) infection:
-for the treatment of varicella (chickenpox) infection in immunocompetent patients:
Oral dosage:
Adults*: 1 g PO 3 times daily for 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
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:
Adults: 1 g PO 3 times daily for 5 to 7 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).
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).
-for the treatment of severe or complicated varicella (chickenpox) infection* in immunocompromised patients as stepdown therapy from IV acyclovir:
Oral dosage:
Adults: 1 g PO 3 times daily for a total treatment course of 7 to 10 days.
Adolescents: 1 g PO 3 times daily for a total treatment course of 7 to 10 days.

For the adjunctive treatment of Bell's palsy* in combination with steroids:
Oral dosage:
Adults: 500 mg PO 2 times daily for 5 days or 1,000 mg PO 3 times daily for 7 days in combination with an oral corticosteroid. Guidelines suggest an antiviral plus oral corticosteroid within 72 hours of symptom onset to modestly increase probability of functional facial nerve recovery.

For the treatment and prophylaxis of encephalitis* due to B virus (cercopithecine herpesvirus) infection*:
Oral dosage:
Adults: 1 g PO every 8 hours for 14 days is recommended as primary therapy by the Infectious Diseases Society of America (IDSA) based on case reports. Further administration of valacyclovir for suppression of latent infection may also be considered.

For post-exposure varicella (chickenpox) infection prophylaxis* in immunocompromised patients:
Oral dosage:
Adults: 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.
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.
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.

For the treatment of herpes simplex ocular infection*, including herpes simplex virus epithelial keratitis*, herpes simplex virus stromal keratitis*, and herpes simplex virus endothelial keratitis*:
-for the treatment of dendritic epithelial keratitis:
Oral dosage:
Adults: 500 mg PO twice daily for 7 to 10 days.
-for the treatment of geographic epithelial keratitis:
Oral dosage:
Adults: 1 g PO 3 times daily for 14 to 21 days.
-for the treatment of non-necrotizing stromal keratitis:
Oral dosage:
Adults: 500 mg PO once daily plus topical ophthalmic steroid for at least 10 weeks.
-for the treatment of necrotizing stromal keratitis:
Oral dosage:
Adults: 1 g PO 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 500 mg PO once daily for the duration of topical ophthalmic steroid use.
-for the treatment of endothelial keratitis:
Oral dosage:
Adults: 500 mg PO twice daily or 1 g PO 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 500 mg PO once daily for the duration of topical ophthalmic steroid use.

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:
Adults: 1 g PO 3 times daily for 7 days. Initiate therapy within 48 to 72 hours of rash onset.
Children and Adolescents 12 to 17 years*: 1 g PO 3 times daily 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:
Adults: 1 g PO 3 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.
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:
-Adults
4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting longer than one day.
-Geriatric
4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting longer than one day.
-Adolescents
4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting longer than one day.
-Children
12 years: 4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting longer than one day.
2 to 11 years: 60 mg/kg/day PO (Max: 3 g/day).
1 year: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary.

Patients with Renal Impairment Dosing
FDA-approved dosage adjustments in adults:
CrCl 50 mL/min and higher: No dosage adjustment needed.
CrCl 30 to 49 mL/min: For regimens of 1 g PO every 8 hours, change to 1 g PO every 12 hours. For one-day treatment of herpes labialis, give 1 g PO every 12 hours for 2 doses. Other regimens do not require a dosage adjustment.
CrCl 10 to 29 mL/min: 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, give 500 mg PO every 12 hours for 2 doses.
CrCl less than 10 mL/min: 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, give 500 mg PO for 1 dose.

Pediatric dosage adjustment recommendations based on a usual dosage of 20 mg/kg/dose PO every 8 hours (Max: 3 g/day):
GFR 50 ml/min/1.73m2 and higher No dosage adjustment needed.
GFR 30 to 49 ml/min/1.73m2: 20 mg/kg/dose PO every 12 hours.
GFR 10 to 29 ml/min/1.73m2: 20 mg/kg/dose PO every 24 hours.
GFR < 10 ml/min/1.73m2: 10 mg/kg/dose PO every 24 hours.

Intermittent hemodialysis
Patients should receive the recommended dosage of valacyclovir after dialysis.

Peritoneal dialysis
FDA-approved labeling 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 500 mg PO every 24 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 and intravenously administered agent.

*non-FDA-approved indication

Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as valacyclovir, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.

Aldesleukin, IL-2: (Moderate) Aldesleukin, IL 2 may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects, such as valacyclovir, with Aldesleukin, IL 2 may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin, IL 2 treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.

Aminoglycosides: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with valacyclovir. Carefully monitor renal function during concomitant therapy.

Amphotericin B lipid complex (ABLC): (Moderate) Concurrent use of amphotericin B and other nephrotoxic medications, including valacyclovir, may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Dosage reduction may be necessary if renal impairment occurs.

Amphotericin B liposomal (LAmB): (Moderate) Concurrent use of amphotericin B and other nephrotoxic medications, including valacyclovir, may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Dosage reduction may be necessary if renal impairment occurs.

Amphotericin B: (Moderate) Concurrent use of amphotericin B and other nephrotoxic medications, including valacyclovir, may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Dosage reduction may be necessary if renal impairment occurs.

Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as valacyclovir, as the risk of renal impairment may be increased.

Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including valacyclovir, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are administered concurrently.

Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as valacyclovir, is contraindicated. Valacyclovir should be discontinued at least 7 days prior to beginning cidofovir.

Cimetidine: (Minor) Cimetidine may cause a reduction in the clearance of acyclovir. The clinical significance of these pharmacokinetic interactions is unknown; however, no dosage adjustments are recommended for patients with normal renal function.

Cisplatin: (Moderate) Closely monitor renal function if concomitant use with cisplatin and valacyclovir is necessary. Cisplatin can cause nephrotoxicity. Valacyclovir can cause renal impairment or renal failure, which may be additive when used with cisplatin.

Clindamycin: (Moderate) Concomitant use of valacyclovir and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

Colistin: (Moderate) Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including valacyclovir, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.

Cyclosporine: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as valacyclovir. Monitor renal function and fluid status carefully.

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.

Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Emtricitabine: (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Monitor for valacyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase valacyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as valacyclovir and emtricitabine, may increase the risk of adverse reactions.

Entecavir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including valacyclovir.

Ethiodized Oil: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Foscarnet: (Major) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents, such as valacyclovir. Avoid concurrent use, unless the potential benefits outweigh the risks to the patient.

Fosphenytoin: (Minor) The addition of valacyclovir to phenytoin may lead to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Clinicians should be prepared to make adjustments in phenytoin or fosphenytoin dosing if valacyclovir therapy is added or discontinued.

Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like valacyclovir. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.

Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like valacyclovir. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.

Inotersen: (Moderate) Use caution with concomitant use of inotersen and valacyclovir due to the risk of glomerulonephritis and nephrotoxicity.

Iodixanol: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Iohexol: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Iomeprol: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Ionic Contrast Media: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Iopamidol: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Iopromide: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Ioversol: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Isosulfan Blue: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.

Lithium: (Moderate) Consider starting with a lower lithium dose and monitor lithium concentrations and for signs and symptoms of lithium toxicity during concomitant valacyclovir use. The risk of lithium toxicity is increased with concomitant use of medications that affect kidney function, such as valacyclovir.

Mannitol: (Major) Avoid use of mannitol and valacyclovir, if possible. Concomitant administration of nephrotoxic drugs, such as valacyclovir, increases the risk of renal failure after administration of mannitol.

Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) If possible, discontinue valacyclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. In patients with HIV, guidelines recommend waiting at least 72 hours after the last dose of valacyclovir before administering varicella vaccines. Also, do not administer valacyclovir for at least 14 days after vaccination. Concurrent administration of any of the varicella-zoster virus vaccines (Zostavax, Varivax, ProQuad) with antiviral medications known to be effective against varicella zoster virus has not been evaluated. Therefore, when possible, a washout period between the use of the antiviral medication and the vaccines is recommended. Valacyclovir has a relatively short serum half-life and is quickly cleared from the body. Refer to the most recent Center for Disease control guidance if concurrent use is necessary.

Methotrexate: (Major) Avoid concomitant use of methotrexate with valacyclovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Valacyclovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with valacyclovir may result in decreased renal function as well as increased methotrexate plasma concentrations.

Mycophenolate: (Moderate) Valacyclovir, a prodrug of acyclovir, when added to a regimen of MMF, cyclosporine, and prednisolone caused neutropenia. The acyclovir trough concentration was 4.5 mg/L, which is in the upper range of the EC(50) for antiviral activity. Cessation of valacyclovir led to immediate recovery of the neutrophil count and an increased concentration of mycophenolic acid (from 0.85 to 1.93 mg/L). Coadministration of mycophenolate mofetil (MMF) and acyclovir to healthy volunteers resulted in no significant change in mycophenolic acid concentrations or AUC. However, the systemic exposure of the glucuronide metabolite of mycophenolate (MPAG) and of acyclovir was increased 10.6% and 21.9%, respectively. Blood cell count monitoring is recommended. The risk of adverse effects (e.g., leukopenia) from concomitant use may be greater in patients with renal impairment, as MPAG and acyclovir concentrations undergo renal tubular secretion. The potential exists for the two drugs to compete for tubular secretion, which could further increase the concentration of both drugs in patients with renal dysfunction.

Non-Ionic Contrast Media: (Moderate) Concomitant use of valacyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.

Nonsteroidal antiinflammatory drugs: (Moderate) Monitor patients for signs of worsening renal function during coadministration of valacyclovir and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.

Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with valacyclovir due to the risk of increased oxaliplatin-related adverse reactions. Valacyclovir is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents.

Phenytoin: (Minor) The addition of valacyclovir to phenytoin may lead to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Clinicians should be prepared to make adjustments in phenytoin dosing if valacyclovir therapy is added or discontinued.

Probenecid: (Moderate) Probenecid can reduce the renal tubular secretion of valacyclovir when these agents are coadministered, causing an increase in the serum concentration and elimination half-life of valacyclovir.

Probenecid; Colchicine: (Moderate) Probenecid can reduce the renal tubular secretion of valacyclovir when these agents are coadministered, causing an increase in the serum concentration and elimination half-life of valacyclovir.

Tacrolimus: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including valacyclovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.

Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.

Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.

Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.

Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.

Vancomycin: (Moderate) Closely monitor renal function if concomitant use with valacyclovir and vancomycin is necessary. Both drugs can cause nephrotoxicity, which may be additive when used together.

Varicella-Zoster Virus Vaccine, Live: (Major) If possible, discontinue valacyclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. In patients with HIV, guidelines recommend waiting at least 72 hours after the last dose of valacyclovir before administering varicella vaccines. Also, do not administer valacyclovir for at least 14 days after vaccination. Concurrent administration of any of the varicella-zoster virus vaccines (Zostavax, Varivax, ProQuad) with antiviral medications known to be effective against varicella zoster virus has not been evaluated. Therefore, when possible, a washout period between the use of the antiviral medication and the vaccines is recommended. Valacyclovir has a relatively short serum half-life and is quickly cleared from the body. Refer to the most recent Center for Disease control guidance if concurrent use is necessary.

Voclosporin: (Moderate) Concomitant use of voclosporin and valacyclovir may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

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.

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.

Other
HIV infection
Valacyclovir pharmacokinetic profiles were not significantly different in HIV-infected patients and non-HIV infected volunteers.