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  • CLASSES

    Nucleoside and Nucleotide DNA Polymerase Inhibitor Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antiviral agent; prodrug of acyclovir
    Used to treat chickenpox, herpes zoster, herpes labialis (cold sores), and genital herpes
    Formulated to improve oral bioavailability with less frequent dosing than oral acyclovir

    COMMON BRAND NAMES

    Valtrex

    HOW SUPPLIED

    Valacyclovir/Valacyclovir Hydrochloride/Valtrex Oral Tab: 1g, 500mg

    DOSAGE & INDICATIONS

    For the treatment of herpes simplex virus infection, including herpes labialis and herpes genitalis.
    For the treatment of herpes labialis (i.e., cold sores).
    Oral dosage
    Adults

    2 g PO every 12 hours for 2 doses starting at the first sign or symptom of lesions. For HIV-infected patients, 1 g PO every 12 hours for 5 to 10 days is recommended by guidelines. There are no data supporting the effectiveness of beginning treatment 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 2 doses starting at the first sign or symptom of lesions. For HIV-infected adolescent patients, 1 g PO every 12 hours for 5 to 10 days is recommended by guidelines. There are no data supporting the effectiveness of beginning treatment 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, including HIV-infected patients†.
    Oral dosage
    Adults

    1 g PO twice daily for 10 days starting at the first sign or symptom of lesions, preferably within 48 hours of onset. The CDC recommends this same dose for 7 to 10 days; treatment may be extended if healing is not complete after 10 days. For HIV-infected patients, 1 g PO every 12 hours for 5 to 10 days is recommended. There are no data supporting the effectiveness of beginning treatment more than 72 hours after the onset of signs and symptoms.

    Adolescents†

    1 g PO twice daily for 10 days starting at the first sign or symptom of lesions, preferably within 48 hours of onset. The CDC recommends this same dose for 7 to 10 days; treatment may be extended if healing is not complete after 10 days. For HIV-infected patients, 1 g PO every 12 hours for 5 to 14 days is recommended. There are no data supporting the effectiveness of beginning treatment more than 72 hours after the onset of signs and symptoms.

    Children†

    Limited data available. 40 mg/kg/day PO in 2 divided doses for patients weighing less than 45 kg and 1 g PO every 12 hours for patients weighing 45 kg or more is recommended by the American Academy of Pediatrics (AAP); treat for 7 to 10 days. Limited data suggest 20 to 25 mg/kg/dose PO given 2 to 3 times per day may produce similar serum concentrations as compared to adults.

    For the treatment of recurrent herpes genitalis, including HIV-infected patients†.
    Oral dosage
    Adults

    500 mg PO twice daily for 3 days starting at the first sign or symptom of lesions, preferably within 24 hours of onset. The CDC recommends this same dose or 1 g PO once daily for 5 days. For HIV-infected patients, 1 g PO every 12 hours for 5 to 10 days is recommended by guidelines. There are no data supporting the effectiveness of beginning treatment more than 24 hours after the onset of symptoms.

    Adolescents†

    500 mg PO twice daily for 3 days starting at the first sign or symptom of lesions, preferably within 24 hours of onset. The CDC recommends this same dose or 1 g PO once daily for 5 days. For HIV-infected patients, 1 g PO every 12 hours for 5 to 14 days is recommended by guidelines. There are no data supporting the effectiveness of beginning treatment more than 24 hours after the onset of symptoms.

    For the treatment of herpes zoster (shingles) infection.
    NOTE: Valacyclovir is not approved for the treatment of disseminated herpes zoster infections.
    Oral dosage
    Adults

    1 g PO 3 times daily for 7 days in immunocompetent patients starting at the first sign or symptom, preferably within 48 hours of onset. Efficacy of treatment initiation after 72 hours of sign/symptom onset has not been established. In HIV-infected patients with localized infections, guidelines recommend treating for 7 to 10 days; a longer duration of therapy may be required if lesions are slow to resolve. In HIV-infected patients with extensive cutaneous lesions or visceral involvement, guidelines recommend as stepdown therapy after IV acyclovir to complete a 10 to 14 day course.

    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. In HIV-infected patients with localized infections, guidelines recommend treating for 7 to 10 days; a longer duration of therapy may be required if lesions are slow to resolve. In HIV-infected patients with extensive cutaneous lesions or visceral involvement, guidelines recommend as stepdown therapy after IV acyclovir to complete a 10 to 14 day course.

    For the treatment of varicella (chickenpox) infection.
    Oral dosage
    Adults†

    The HIV guidelines recommend 1 g PO 3 times daily for 5 to 7 days for uncomplicated infections; 1 g PO 3 times daily as stepdown therapy from IV acyclovir for complicated infections for a total treatment course of 7 to 10 days.[34362]

    Adolescents

    20 mg/kg/dose PO 3 times daily (Max: 3 g/day) for 5 days. Start treatment at the first sign or symptom, preferably within 24 hours of rash onset.[29970] The HIV guidelines recommend 1 g PO 3 times daily for 5 to 7 days for uncomplicated infections; 1 g PO 3 times daily as stepdown therapy from IV acyclovir for complicated infections, for a total treatment course of 7 to 10 days.[34362]

    Children 2 to 12 years

    20 mg/kg/dose PO 3 times daily (Max: 3 g/day) for 5 days in immunocompetent patients. Start treatment at the first sign or symptom, preferably within 24 hours of rash onset.

    For the treatment of acute retinal necrosis (ARN)† due to varicella-zoster virus in HIV-infected patients.
    Oral dosage
    Adults

    After initial therapy with intravenous acyclovir and intravitreal ganciclovir, start 1 g PO 3 times daily for at least 14 weeks.

    Adolescents

    After initial therapy with intravenous acyclovir and intravitreal ganciclovir, start 1 g PO 3 times daily for at least 14 weeks.

    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 herpes genitalis prophylaxis or for secondary herpes simplex infection prophylaxis†.
    For suppressive therapy of recurrent herpes genitalis in all patients or for secondary herpes simplex infection prophylaxis† in HIV-patients for frequent or severe recurrences.
    Oral dosage
    Adults

    In immunocompetent patients, 1 g PO once daily. In patients with a history of 9 or fewer recurrences per year, 500 mg PO once daily may be given.[29970] 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 of valacyclovir beyond 1 year have not been established.[59799] In HIV-infected patients, 500 mg PO twice daily.[29970] [34362] [59799] The safety and efficacy of therapy beyond 6 months have not been established.[29970]

    Adolescents†

    500 mg or 1 g PO once daily is recommended by the CDC; the 500 mg/day regimen may be less effective in patients who have very frequent recurrences (i.e., 10 or more episodes/year). For HIV-infected patients, give 500 mg PO twice daily. Suppressive therapy is usually continued indefinitely (without regard to CD4 count).

    Children†

    500 mg PO twice daily is recommended in the HIV guidelines for children old enough to receive adult dosing; acyclovir is the drug of choice for younger children.

    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 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 kidney transplantation.
    Oral dosage
    Adults

    2 g PO four times daily for 3 to 6 months as a prophylaxis option.[57951] [57952] 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.[25699] Additional studies suggest that valacyclovir may be as effective as oral ganciclovir.[57971] [57972]

    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 heart transplantation.
    Oral dosage
    Adults

    Not recommended as an option by guidelines.[57951] [57952] 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.[57973]

    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.[56392] [59246] [59248] [59249] Guidelines suggest an antiviral plus oral corticosteroid within 72 hours of symptom onset to modestly increase probability of functional facial nerve recovery.[55538] [59237]

    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 has not been studied in HIV-infected adults.

    Infants 3 to 11 months, Children, and Adolescents

    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 immunoglobulin (VariZIG) is not feasible. Due to the lack of data of valacyclovir/acyclovir prophylaxis in HIV-infected patients, other experts consider it prudent to wait until rash appears to begin treatment. Post-exposure prophylaxis is indicated for HIV-infected children 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is necessary.

    Renal Impairment

    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.

    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).

    STORAGE

    Valtrex:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Acyclovir hypersensitivity, famciclovir hypersensitivity, ganciclovir hypersensitivity, penciclovir hypersensitivity, valacyclovir hypersensitivity, valganciclovir hypersensitivity

    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.

    Renal failure, renal impairment

    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.

    Geriatric

    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.

    Dehydration

    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.

    Children, infants, neonates

    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.

    Pregnancy

    Clinical data regarding 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 1st 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 1st 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 3rd trimester.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 0.6-18.0
    elevated hepatic enzymes / Delayed / 1.0-16.0
    depression / Delayed / 5.0-7.0
    thrombocytopenia / Delayed / 0.1-3.0
    dehydration / Delayed / 2.0-2.0
    anemia / Delayed / 0.2-0.8
    hallucinations / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    delirium / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    ataxia / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    mania / Early / Incidence not known
    dyspnea / Early / Incidence not known
    psychosis / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    headache / Early / 11.0-38.0
    pharyngitis / Delayed / 16.0-16.0
    nausea / Early / 4.0-15.0
    abdominal pain / Early / 3.0-11.0
    sinusitis / Delayed / 9.0-9.0
    fatigue / Early / 8.0-8.0
    dysmenorrhea / Delayed / 5.0-8.0
    rash / Early / 8.0-8.0
    vomiting / Early / 3.0-6.0
    arthralgia / Delayed / 5.0-6.0
    diarrhea / Early / 5.0-5.0
    dizziness / Early / 2.0-4.0
    fever / Early / 4.0-4.0
    rhinorrhea / Early / 2.0-2.0
    agitation / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    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 cholesteryl sulfate complex (ABCD): (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 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 serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    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: (Severe) 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.
    Colchicine; 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.
    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 serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    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: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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; 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 serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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 Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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.
    Emtricitabine: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valacyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valacyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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.
    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.
    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.
    Gallium Ga 68 Dotatate: (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.
    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.
    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.
    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) Closely monitor renal function and monitor for signs and symptoms of lithium toxicity if concurrent administration with valacyclovir is necessary. Valacyclovir can cause nephrotoxicity. Lithium is renally eliminated; concomitant use of drugs that affect kidney function can increase lithium serum concentrations.
    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. 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: (Moderate) Closely monitor renal function if concomitant use with valacyclovir and methotrexate is necessary. Both drugs can cause nephrotoxicity, which may be additive when used together.
    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.
    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.
    Polymyxins: (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.
    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.
    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.
    Telbivudine: (Moderate) Drugs that alter renal function such as valacyclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    Tenofovir, PMPA: (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. 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Clinical data regarding 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 1st 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 1st 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 3rd 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.

    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 the monophosphate by viral thymidine kinase (TK), then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Acyclovir triphosphate stops replication of herpes viral DNA by the following 3 mechanisms: competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.
     
    Herpes virus DNA polymerases differ in sensitivity to acyclovir. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral thymidine kinase. Acyclovir is effective only against actively replicating viruses; therefore, it does not eliminate the latent herpes virus genome. Uninfected cells show only minimal phosphorylation of acyclovir, and there is only a small amount of acyclovir taken up into these cells. The concentration of acyclovir triphosphate is 40- to 100- times higher in HSV-infected cells than non-infected cells. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.
     
    Viral resistance to acyclovir may occur due to loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA-polymerase sensitivity. The alterations in these enzymes occur due to point mutations or base insertions or deletions in the specific genes. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents activated by thymidine kinase (e.g., foscarnet, famciclovir, and penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in immunocompromised patients. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.

    PHARMACOKINETICS

    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.

    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.