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  • CLASSES

    Other Systemic Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

     
    Oral antiviral agent; prodrug of acyclovir
    Used to treat chickenpox, herpes zoster, and herpes simplex infections
    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, and including HIV-infected patients†.
    For the treatment of herpes labialis (i.e., cold sores).
    Oral dosage
    Adults, Adolescents, and Children 12 years and older

    2 g PO every 12 hours for 2 doses starting at the first sign or symptom of lesions. For HIV-infected adult and adolescent patients, 1 g PO every 12 hours for 5 to 10 days is recommended by the HIV 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.
    Oral dosage
    Adults and 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 less than 45 kg and 1 g PO every 12 hours for patients 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 and 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 the HIV 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 three times a day 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, the HIV guidelines recommend treating for 7—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, the guidelines recommend as stepdown therapy after IV acyclovir to complete a 10—14 day course.

    Adolescents

    1 g PO 3 times a day for 7 days. Initiate therapy at first sign or symptom; therapy is most effective if initiated within 48 hours of rash onset. For HIV-infected patients, the HIV guidelines recommend to treat for 7—10 days for localized infections; a longer duration of therapy may be required if lesions are slow to resolve. In patients with extensive cutaneous lesions or visceral involvement, the guidelines recommend as stepdown therapy after IV acyclovir to complete a 10—14 day course.

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

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

    Adolescents

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

    Children >= 2 years

    20 mg/kg/dose PO three times daily for 5 days in immunocompetent patients (Max: 3 g/day). 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 10—14 days of IV and intravitreal therapy, 1 g PO three times daily for 6 weeks is recommended by the HIV guidelines.

    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 recurrences per year, 500 mg PO once daily may be given. 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. In HIV-infected patients, 500 mg PO twice daily. The safety and efficacy of therapy beyond 6 months have not been established.

    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—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 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. 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 < 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 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 the adjunctive treatment of Bell's palsy† in combination with steroids.
    Oral dosage
    Adults

    500 mg PO 2 times daily for 5 days or 1000 mg PO 3 times daily for 7 days in combination with an oral corticosteroid. Clinical practice guidelines suggest an antiviral plus oral corticosteroid within 72 hours of symptom onset to modestly increase probability of functional facial nerve recovery.

    For post-exposure varicella (chickenpox) infection prophylaxis† to prevent primary infection in HIV-infected patients.
    Oral dosage
    Adults and Adolescents

    1 g PO three times daily for 5—7 days beginning 7—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 and adolescents.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting > 1 day.

    Elderly

    4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting > 1 day.

    Adolescents

    4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting > 1 day.

    Children

    >= 12 years: 4 g/day PO for one-day treatment regimens or 3 g/day for regimens lasting > 1 day.
    >= 2 years and < 12 years: 60 mg/kg/day PO, not to exceed 3 g/day PO.
    < 2 years: 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: No dosage adjustment needed.
    CrCl 30—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 x 2 doses.  Other regimens do not require a dosage adjustment.
    CrCl 10—29 ml/min: For regimens of 1 g PO every 8—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 x 2 doses.
    CrCl < 10 ml/min: For regimens of 1 g PO every 8—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 x 1 dose.
     
    Other dosage adjustment recommendations:
    CrCl > 50 ml/min: No dosage adjustment needed.
    CrCl 10—50 ml/min: Give the full dose every 12—24 hours depending on indication.
    CrCl < 10 ml/min: 500 mg 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 caplets into a fine powder (five 500 mg caplets for 25 mg/ml suspension, ten 500 mg caplets 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—8 degrees C, 36—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

    Valacyclovir has been classified as FDA pregnancy category B. No complete or well-controlled pregnancy studies have been performed in humans. Acyclovir, the active component of valacyclovir, was not found to be teratogenic in standard animal studies. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for specific defects or to permit definitive conclusions regarding the safety of acyclovir in pregnant women. Valacyclovir should be avoided during pregnancy unless the potential benefits outweigh the possible risks to the fetus.

    Breast-feeding

    According to the manufacturer, valacyclovir should be administered to a nursing mother with caution and only when indicated. 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. The 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
    erythema multiforme / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    coma / Early / Incidence not known
    anaphylactoid reactions / Rapid / 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
    hepatitis / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    mania / Early / Incidence not known
    hypertension / Early / Incidence not known
    dyspnea / Early / 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
    dysmenorrhea / Delayed / 5.0-8.0
    fatigue / Early / 8.0-8.0
    rash (unspecified) / 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
    photosensitivity / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have 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, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valacyclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valacyclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have 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, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valacyclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have 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, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valacyclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    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.
    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.
    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.
    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.
    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.
    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) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have 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, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir Alafenamide: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have 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, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir, PMPA: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valacyclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    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

    Valacyclovir has been classified as FDA pregnancy category B. No complete or well-controlled pregnancy studies have been performed in humans. Acyclovir, the active component of valacyclovir, was not found to be teratogenic in standard animal studies. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for specific defects or to permit definitive conclusions regarding the safety of acyclovir in pregnant women. Valacyclovir should be avoided during pregnancy unless the potential benefits outweigh the possible risks to the fetus.

    According to the manufacturer, valacyclovir should be administered to a nursing mother with caution and only when indicated. 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. The 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.[51534] 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., ganciclovir or 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—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—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 < 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—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—2 g PO four times daily yields plasma acyclovir concentrations and AUC levels similar to that obtained after IV administration of acyclovir 5—10 mg/kg every 8 hours. As a result of improved oral bioavailability, valacyclovir requires less frequent dosing than acyclovir.