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  • CLASSES

    Nucleoside and Nucleotide DNA Polymerase Inhibitor Antivirals
    Topical Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic antiviral with activity against herpes simplex virus type 1 and 2 and varicella-zoster virus
    Used to treat herpes labialis, herpes genitalis, herpes simplex encephalitis, herpes simplex keratitis, neonatal herpes infection, chickenpox (varicella), shingles (zoster)
    Potent activity against herpes simplex viruses type 1 and 2 and much less activity against varicella-zoster virus

    COMMON BRAND NAMES

    Sitavig, Zovirax, Zovirax Cream, Zovirax Ointment, Zovirax Powder, Zovirax Suspension

    HOW SUPPLIED

    Acyclovir/Acyclovir Sodium Intravenous Inj Sol: 1mL, 50mg
    Acyclovir/Acyclovir Sodium/Zovirax/Zovirax Powder Intravenous Inj Pwd F/Sol: 500mg
    Acyclovir/Zovirax Oral Cap: 200mg
    Acyclovir/Zovirax Oral Tab: 400mg, 800mg
    Acyclovir/Zovirax/Zovirax Cream Topical Cream: 5%
    Acyclovir/Zovirax/Zovirax Ointment Topical Ointment: 5%
    Acyclovir/Zovirax/Zovirax Suspension Oral Susp: 5mL, 200mg
    Sitavig Buccal Tablet, SL: 50mg

    DOSAGE & INDICATIONS

    For the treatment of neonatal herpes simplex virus infection.
    For premptive therapy for asymptomatic neonates exposed to active genital herpes lesions during delivery†.
    Intravenous dosage
    Neonates

    20 mg/kg/dose IV every 8 hours. For neonates born to mothers with no history of genital HSV preceding pregnancy, acyclovir should be initiated by 24 hours of age prior to HSV virology testing results. Acyclovir therapy may be discontinued if virology studies are negative. If virology studies are positive, or it is a first episode of primary or nonprimary maternal genital herpes infection, continue acyclovir for 10 days. For neonates born to mothers with a maternal history of genital HSV preceding pregnancy, acyclovir should be initiated for neonates with positive virology studies and continued for 10 days.

    For the treatment of localized disease of the skin, eyes, and/or mouth (SEM disease).
    Intravenous dosage
    Infants 1 to 4 months

    20 mg/kg/dose IV every 8 hours for 14 days, followed by oral acyclovir suppressive therapy for 6 months.

    Neonates 34 weeks postmenstrual age and older

    20 mg/kg/dose IV every 8 hours for 14 days, followed by oral acyclovir suppressive therapy for 6 months.

    Neonates younger than 34 weeks postmenstrual age

    20 mg/kg/dose IV every 8 hours for 14 days, followed by oral acyclovir suppressive therapy for 6 months. The FDA-approved dose is 20 mg/kg/dose IV every 12 hours.

    For the treatment of CNS or disseminated disease.
    Intravenous dosage
    Infants 1 to 4 months

    20 mg/kg/dose IV every 8 hours for 21 days, followed by oral acyclovir suppressive therapy for 6 months. If evidence of CNS disease is present at the initiation of therapy, repeat cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) near the end of the 21-day treatment course. If positive, continue acyclovir for 7 additional days. Repeat CSF HSV PCR again near the anticipated end of the treatment course to determine whether cessation of therapy is appropriate.

    Neonates 34 weeks postmenstrual age and older

    20 mg/kg/dose IV every 8 hours for 21 days, followed by oral acyclovir suppressive therapy for 6 months. If evidence of CNS disease is present at the initiation of therapy, repeat cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) near the end of the 21-day treatment course. If positive, continue acyclovir for 7 additional days. Repeat CSF HSV PCR again near the anticipated end of the treatment course to determine whether cessation of therapy is appropriate.

    Neonates younger than 34 weeks postmenstrual age

    20 mg/kg/dose IV every 8 hours for 21 days, followed by oral acyclovir suppressive therapy for 6 months. The FDA-approved dose is 20 mg/kg/dose IV every 12 hours. If evidence of CNS disease is present at the initiation of therapy, repeat cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) near the end of the 21-day treatment course. If positive, continue acyclovir for 7 additional days. Repeat CSF HSV PCR again near the anticipated end of the treatment course to determine whether cessation of therapy is appropriate.

    For the treatment of viral encephalitis.
    NOTE: For congenital herpes, see neonatal herpes simplex virus infection.
    For the treatment of herpes simplex encephalitis.
    Intravenous dosage

    NOTE: For congenital herpes, see neonatal herpes simplex virus infection.

    Adults

    10 mg/kg/dose IV every 8 hours for 14 to 21 days.[34213] Use ideal body weight when dosing persons with obesity.[34408]

    Children and Adolescents 12 to 17 years

    10 mg/kg/dose IV every 8 hours for 14 to 21 days.[34213] In persons living with HIV, treat for 21 days.[34361] Use ideal body weight when dosing persons with obesity.[34408]

    Infants and Children 3 months to 11 years

    10 to 15 mg/kg/dose IV every 8 hours for 14 to 21 days.[34213] In persons living with HIV, treat for 21 days.[34361] The FDA-approved dose is 20 mg/kg/dose IV every 8 hours for 10 days.[34408] Use ideal body weight when dosing persons with obesity.[34408]

    Infants 1 to 2 months†

    20 mg/kg/dose IV every 8 hours for 21 days.

    For the treatment of varicella-zoster encephalitis†.
    Intravenous dosage
    Adults

    10 to 15 mg/kg/dose IV every 8 hours for 10 to 14 days.[34213] Use ideal body weight when dosing persons with obesity.[34408]

    Infants, Children, and Adolescents 5 months to 17 years

    10 to 15 mg/kg/dose IV every 8 hours for 10 to 14 days.[34213] Use ideal body weight when dosing persons with obesity.[34408]

    Infants 1 to 4 months

    20 mg/kg/dose IV every 8 hours for 10 to 14 days.

    For the treatment of encephalitis due to B virus (cercopithecine herpesvirus) infection† as an alternative to valacyclovir.
    Intravenous dosage
    Adults

    12.5 to 15 mg/kg/dose IV every 8 hours for 10 to 14 days.[34213] Use ideal body weight when dosing persons with obesity.[34408]

    For the empiric treatment of viral encephalitis†.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours. Use ideal body weight when dosing persons with obesity.[34408]

    Infants, Children, and Adolescents 5 months to 17 years

    10 mg/kg/dose IV every 8 hours. Use ideal body weight when dosing persons with obesity.[34408]

    Infants 1 to 4 months

    20 mg/kg/dose IV every 8 hours.

    Neonates

    20 mg/kg/dose IV every 8 hours.

    For the treatment of herpes labialis caused by herpes simplex virus.
    For the initial treatment of herpes labialis in immunocompromised patients, including persons living with HIV.
    Oral dosage†
    Adults

    400 mg PO 3 times daily for 5 to 10 days or until clinical resolution.

    Adolescents

    400 mg PO 3 times daily for 5 to 10 days or until clinical resolution.

    Infants and Children

    20 mg/kg/dose (Max: 400 mg/dose) PO 4 times daily for 7 to 10 days or until clinical resolution for mild symptomatic gingivostomatitis.[34361]

    Intravenous dosage
    Adults

    5 mg/kg/dose IV every 8 hours for 7 days. Once lesions begin to regress, a change to oral dosing is recommended. [34408] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408]

    Children and Adolescents 12 to 17 years

    5 mg/kg/dose IV every 8 hours for 7 days. Once lesions begin to regress, a change to oral dosing is recommended. [34408] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar considerations should be given to pediatric patients.

    Infants and Children 1 to 11 years

    5 to 10 mg/kg/dose IV every 8 hours for 7 days. Once lesions begin to regress, a change to oral dosing is recommended. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar considerations should be given to pediatric patients.

    Topical dosage (Ointment)
    Adults

    Apply a sufficient quantity of ointment to adequately cover all lesions every 3 hours, 6 times daily, for 7 days. The dose size per application will vary depending upon the lesion area but should be approximately 0.5-inch ribbon of ointment per 4 square inches of surface area. Therapy should be initiated as early as possible after signs and symptoms onset.

    For the initial treatment of herpes labialis in immunocompetent patients.
    Topical dosage (Cream)
    Adults

    Apply sufficient quantity of cream to cover the lesions 5 times daily for 4 days. Treatment should begin at the first sign or symptom (during the prodrome or when lesions appear).[43519]

    Children and Adolescents 12 to 17 years

    Apply sufficient quantity of cream to cover the lesions 5 times daily for 4 days. Treatment should begin at the first sign or symptom (during the prodrome or when lesions appear).[43519]

    For treatment of recurrent herpes labialis in persons living with HIV†.
    Oral dosage
    Adults

    400 mg PO 3 times daily for 5 to 10 days.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 400 mg/dose) PO 4 times daily for 5 to 7 days.[34361]

    For treatment of recurrent herpes labialis in immunocompetent patients.
    Buccal dosage
    Adults

    One 50-mg buccal tablet applied to the upper gum region as a single dose.

    Oral dosage†
    Adults

    400 mg PO 5 times daily for 5 days.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 400 mg/dose) PO 4 times daily for 5 to 7 days.

    For the treatment of herpes zoster (shingles) infection.
    NOTE: For CNS infections, see encephalitis.
    For the treatment of herpes zoster (shingles) infection in immunocompromised patients.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours for 7 days.[34408] For persons living with HIV and extensive cutaneous lesions or visceral involvement, guidelines recommend 10 mg/kg/dose IV every 8 hours until clinical improvement, followed up by oral therapy (including acyclovir, famciclovir, or valacyclovir) to complete a 10- to 14-day course.[34362] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[34408]

    Children and Adolescents 12 to 17 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days.[34408] For persons living with HIV and extensive cutaneous lesions or visceral involvement, guidelines recommend 10 mg/kg/dose IV every 8 hours until clinical improvement, followed up by oral therapy (including acyclovir, famciclovir, or valacyclovir) to complete a 10- to 14-day course.[34362] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Infants and Children 1 to 11 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days. The FDA-approved dosage regimen is 20 mg/kg/dose IV every 8 hours for 7 to 10 days.[34408] For persons living with HIV and trigeminal nerve involvement or extensive multi-dermatomal zoster, guidelines recommend treating with 10 mg/kg/dose IV every 8 hours until cutaneous lesions and visceral disease are clearly resolving and then switching to oral therapy to complete a 10- to 14-day course.[34361] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Oral dosage
    Adults

    800 mg PO 5 times daily for 7 to 10 days.[28977] For localized lesions in persons living with HIV, guidelines recommend as an alternative but suggest that the duration may be longer if the lesions are slow to resolve. For extensive cutaneous lesions or visceral involvement in persons living with HIV, oral acyclovir may be used as stepdown therapy after IV acyclovir to complete 10 to 14 days of therapy.[34362]

    Adolescents†

    800 mg PO 5 times daily for 7 to 10 days is recommended as an alternative therapy for those with uncomplicated disease. Consider longer duration if lesions are slow to resolve. For extensive cutaneous lesions or visceral involvement in persons living with HIV, oral acyclovir may be used as stepdown therapy after IV acyclovir to complete 10 to 14 days of therapy.[34362]

    Infants† and Children†

    20 mg/kg/dose (Max: 800 mg/dose) PO 4 times daily for 7 to 10 days for uncomplicated disease.[34361]

    For the treatment of herpes zoster (shingles) infection in immunocompetent patients.
    Oral dosage
    Adults

    800 mg PO 5 times daily for 7 to 10 days. Initiate therapy within 48 to 72 hours of rash onset. During trials, therapy was begun within 72 hours of rash onset and was most effective if started within the first 48 hours. Adults older than 50 years showed the greatest benefit.

    Children and Adolescents 12 to 17 years†

    800 mg PO 5 times daily for 5 to 7 days.

    Intravenous dosage†
    Children and Adolescents 2 to 17 years

    10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days. The use of ideal body weight is recommended when dosing obese adults.[34408] Similar consideration should be given to pediatric patients.

    Infants and Children younger than 2 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days.

    For the treatment of varicella (chickenpox) infection.
    For the treatment of varicella (chickenpox) infection in immunocompetent patients.
    Oral dosage
    Adults

    800 mg PO 4 times daily for 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours). Treatment with acyclovir has been shown to shorten the time to healing, reduce the number of lesions, reduce the number of vesicles, and reduce other symptoms such as fever, anorexia, and lethargy.

    Children and Adolescents 2 to 17 years

    20 mg/kg/dose (Max: 800 mg/dose) PO 4 times daily for 5 days.[28977] Initiate therapy at the first sign of symptoms (i.e., within 24 hours). In general, acyclovir is not recommended for routine use for the treatment of varicella infections in otherwise healthy children at low risk for complications. Oral acyclovir should be considered for those at increased risk of moderate to severe varicella, such as unvaccinated adolescents, patients with chronic cutaneous or pulmonary conditions, patients receiving long-term salicylate therapy, and patients receiving short or intermittent courses of corticosteroids.

    Intravenous dosage†

    NOTE: Intravenous acyclovir is recommended for those with severe infection requiring hospitalization, including pregnant patients.

    Adults

    10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.

    Children and Adolescents 2 to 17 years

    10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    For the treatment of varicella (chickenpox) infection in immunocompromised patients.
    Intravenous dosage†
    Adults

    10 mg/kg/dose IV every 8 hours for 7 to 10 days. May switch to oral therapy after defervescence if there is no evidence of visceral involvement. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.

    Adolescents

    10 mg/kg/dose IV every 8 hours for 7 to 10 days. May switch to oral therapy after defervescence if there is no evidence of visceral involvement. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Children 2 to 12 years

    10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days and until there are no new lesions for 48 hours.[34361] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Infants and Children younger than 2 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days and until there are no new lesions for 48 hours.

    Neonates

    10 to 20 mg/kg/dose IV every 8 hours for infants presenting with a varicella infection within the first month of life.

    Oral dosage

    NOTE: Due to poor bioavailability, experts generally recommend against the use of oral acyclovir for varicella infections in immunocompromised patients.

    Adults

    800 mg PO 5 times daily for 5 to 7 days is recommended as an alternative therapy in persons living with HIV and uncomplicated disease. Additionally, oral acyclovir may be used as stepdown therapy after IV acyclovir in severe or complicated cases for a total treatment duration of 7 to 10 days.[34362] The FDA-approved dosage is 800 mg PO 4 times daily for 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).[28977]

    Adolescents

    800 mg PO 5 times daily for 5 to 7 days is recommended as an alternative therapy in persons living with HIV and uncomplicated disease. Additionally, oral acyclovir may be used as stepdown therapy after IV acyclovir in severe or complicated cases for a total treatment duration of 7 to 10 days.[34362] The FDA-approved dosage is 800 mg PO 4 times daily for 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).[28977]

    Children 2 to 12 years

    20 mg/kg/dose (Max: 800 mg/dose) PO 4 times per day for 7 to 10 days and until there are no new lesions for 48 hours. For persons living with HIV, oral acyclovir should only be used for children who are in CDC Immunologic Category 1 or 2 (no or moderate immune suppression) and who have mild varicella disease.[34361] The FDA-approved duration is 5 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).[28977]

    Infants† and Children younger than 2 years†

    20 mg/kg/dose (Max: 800 mg/dose) PO 4 times daily for 7 to 10 days and until there are no new lesions for 48 hours. For persons living with HIV, oral acyclovir should only be used for children who are in CDC Immunologic Category 1 or 2 (no or moderate immune suppression) and who have mild varicella disease. Initiate at first sign of symptoms (i.e., within 24 hours).[34361]

    For the treatment of herpes genitalis caused by herpes simplex virus.
    For the treatment of initial episode of herpes genitalis in immunocompetent patients.
    Oral dosage
    Adults

    400 mg PO 3 times daily for 7 to 10 days or until clinical resolution. The FDA-approved dosage is 200 mg PO every 4 hours, 5 times daily for 10 days.[28977]

    Children† weighing 45 kg or more and Adolescents†

    400 mg PO 3 times daily for 7 to 10 days or until clinical resolution. 

    Infants† and Children† weighing less than 45 kg

    40 to 80 mg/kg/day (Max: 1,200 mg/day) PO in 3 to 4 divided doses for 7 to 10 days or until clinical resolution.

    Intravenous dosage
    Adults

    5 mg/kg/dose IV every 8 hours for 5 days. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Children and Adolescents 12 to 17 years

    5 mg/kg/dose IV every 8 hours for 5 days.[34408] The FDA-approved labeling recommends using ideal body weight when dosing obese adults.[34408] Similar considerations should be given to pediatric patients.

    For the treatment of recurrent herpes genitalis in immunocompetent patients.
    Oral dosage
    Adults

    800 mg PO 3 times daily for 2 days or 800 mg PO twice daily for 5 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. The FDA-approved dosage is 200 mg PO every 4 hours, 5 times daily, for 5 days.

    Children† weighing 45 kg or more and Adolescents†

    800 mg PO 3 times daily for 2 days or 800 mg PO twice daily for 5 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset.

    For the treatment of initial episode of herpes genitalis in immunocompromised patients, including in persons living with HIV.
    Oral dosage
    Adults

    400 mg PO 3 times daily for 7 to 10 days or until clinical resolution. The duration of therapy may be extended if healing is incomplete by day 10.[34362] The FDA-approved dosage is 200 mg PO every 4 hours, 5 times daily for 10 days.[28977]

    Adolescents†

    400 mg PO 3 times daily for 7 to 10 days or until clinical resolution.[34362]

    Intravenous dosage†
    Adults

    5 mg/kg/dose IV every 8 hours. Once lesions begin to regress, a change to oral dosing is recommended.[34362] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Adolescents

    5 mg/kg/dose IV every 8 hours. Once lesions begin to regress, a change to oral dosing is recommended.[34362] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. Similar considerations should be given to pediatric patients.

    Topical dosage (Ointment)
    Adults

    Apply sufficient quantity of ointment to adequately cover all lesions every 3 hours, 6 times daily, for 7 days. The dose size per application will vary depending upon the lesion area but should approximate 0.5-inch ribbon of ointment per 4 square inches of surface area. Treatment should begin at the first sign or symptom.

    For the treatment of recurrent herpes genitalis in persons living with HIV.
    Oral dosage
    Adults

    400 mg PO 3 times daily for 5 to 10 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. The FDA-approved dosage is 200 mg PO every 4 hours, 5 times daily, for 5 days, initiated at the first sign or symptom or recurrence.

    Adolescents†

    400 mg PO 3 times daily for 5 to 10 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset.

    For secondary herpes genitalis prophylaxis (i.e., long-term suppressive therapy) in patients with frequent or severe recurrences.
    Oral dosage
    Adults

    400 mg PO twice daily. In persons living with HIV, guidelines suggest suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually. Alternative regimens have ranged from 200 mg PO 3 times daily to 200 mg PO 5 times daily.

    Children and Adolescents 12 to 17 years

    400 mg PO twice daily. In persons living with HIV, guidelines suggest suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually. Alternative regimens have ranged from 200 mg PO 3 times daily to 200 mg PO 5 times daily.

    Infants† and Children† 1 to 11 years

    20 mg/kg/dose (Max: 400 mg/dose) PO twice daily is recommended for persons living with HIV. After a prolonged period (e.g., 1 year) of prophylaxis, consider stopping prophylaxis and assess patient to determine if additional prophylaxis is required. Although level of immune reconstitution should be a consideration, specific CD4 thresholds have not been determined.

    For the treatment of complicated herpes simplex virus infection (e.g., disseminated disease†, pneumonitis†, infection in immunocompromised hosts, and infections requiring hospitalization).
    NOTE: For congenital herpes, see neonatal herpes simplex virus infection; for CNS disease, see encephalitis.
    Oral dosage†
    Adults

    400 mg PO 3 times daily following IV therapy to complete at least 10 days of total therapy or until lesions are completely healed.

    Adolescents

    400 mg PO 3 times daily following IV therapy to complete at least 10 days of total therapy or until lesions are completely healed.

    Children 2 to 12 years

    1,000 mg/day PO divided into 3 to 5 doses following IV therapy to complete at least 10 days of total therapy or until lesions are completely healed.

    Intravenous dosage
    Adults

    5 to 10 mg/kg/dose IV every 8 hours for at least 7 days or until clinical improvement, then oral antiviral therapy to complete at least 10 days of total therapy or until lesions are completely healed.[34408] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[34408]

    Children and Adolescents 12 to 17 years

    5 to 10 mg/kg/dose IV every 8 hours for at least 7 days or until clinical improvement, then oral antiviral therapy to complete at least 10 days of total therapy or until lesions are completely healed. [34408] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Infants and Children 3 months to 11 years

    10 mg/kg/dose IV every 8 hours for at least 7 days or until clinical improvement, then oral antiviral therapy to complete at least 10 days of total therapy or until lesions are completely healed. [34408] For disseminated disease in persons living with HIV, 10 to 15 mg/kg/dose IV every 8 hours for 21 days is recommended.[34361] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Infants 1 to 2 months†

    10 mg/kg/dose IV every 8 hours for at least 7 days or until clinical improvement, then oral antiviral therapy to complete at least 10 days of total therapy or until lesions are completely healed. [34408] For disseminated disease in persons living with HIV, 10 to 15 mg/kg/dose IV every 8 hours for 21 days is recommended.[34361]

    For the treatment of herpes zoster ocular infection (herpes zoster ophthalmicus), including viral conjunctivitis.
    For the treatment of herpes zoster ocular infection in immunocompetent patients.
    Oral dosage
    Adults

    800 mg PO 5 times daily for 7 to 10 days. Initiate therapy within 48 to 72 hours of rash onset. Guidelines recommend famciclovir or valacyclovir.

    Children and Adolescents 12 to 17 years†

    800 mg PO 5 times daily for 7 to 10 days. Initiate therapy within 48 to 72 hours of rash onset.   Guidelines recommend famciclovir or valacyclovir.

    Intravenous dosage†

    NOTE: Intravenous acyclovir therapy is recommended for those with retinitis.

    Adults

    10 mg/kg/dose IV every 8 hours for 7 to 10 days. Transition to oral antiviral therapy when infection is controlled for remainder of 7- to 10-day treatment course.

    Children and Adolescents 12 to 17 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days.  Transition to oral antiviral therapy when infection is controlled for remainder of 7- to 10-day treatment course.

    For the treatment of herpes zoster ocular infection in immunocompromised patients.
    Oral dosage

    NOTE: Oral therapy can be considered for those who are not severely immunosuppressed.

    Adults

    800 mg PO 5 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.    Guidelines recommend famciclovir or valacyclovir.

    Children and Adolescents 12 to 17 years†

    800 mg PO 5 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.   Guidelines recommend famciclovir or valacyclovir.

    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours for 7 to 14 days.  Transition to oral antiviral therapy when infection is controlled for remainder of 7- to 14-day treatment course.

    Children and Adolescents 12 to 17 years

    10 mg/kg/dose IV every 8 hours for 7 to 14 days.  Transition to oral antiviral therapy when infection is controlled for remainder of 7- to 14-day treatment course.

    For neonatal herpes simplex virus infection prophylaxis† (i.e., suppressive therapy) in neonates with any neonatal herpes simplex disease classification.
    Oral dosage
    Neonates and Infants

    300 mg/m2/dose PO 3 times daily for 6 months after initial treatment with IV acyclovir.[51746] The dose should be adjusted each month for growth. Absolute neutrophil counts should be assessed 2 to 4 weeks after suppressive therapy start and then monthly thereafter during treatment.

    For secondary herpes labialis prophylaxis† (i.e., long-term suppressive therapy) in persons living with HIV.
    Oral dosage
    Adults

    400 mg PO twice daily. Suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually.

    Adolescents

    400 mg PO twice daily. Suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually.

    Infants and Children

    20 mg/kg/dose (Max: 400 mg/dose) PO twice daily. After a prolonged period (e.g., 1 year) of prophylaxis, consider stopping prophylaxis and assess patient to determine if additional prophylaxis is required. Although level of immune reconstitution should be a consideration, specific CD4 thresholds have not been determined.[34361]

    For primary herpes simplex infection prophylaxis† in immunocompromised hosts who are HSV-seropositive.
    Oral dosage
    Adults

    400 to 800 mg PO twice daily to prevent early reactivation or 800 mg PO twice daily to prevent late reactivation; administer during the period of risk. For prevention of early reactivation in HCT recipients, initiate therapy beginning 1 day prior to transplant and continue until marrow engraftment. For prevention of late reactivation among HCT recipients, treat during the first year after HCT.

    Infants, Children, and Adolescents

    80 mg/kg/day (Max: 1,600 mg/day) PO in 2 to 3 divided doses during the period of risk. For prevention of early reactivation in HCT recipients, initiate therapy beginning 1 day prior to transplant and continue until marrow engraftment. For prevention of late reactivation among HCT recipients, treat during the first year after HCT.

    Intravenous dosage
    Adults

    250 mg/m2/dose or 5 mg/kg/dose IV every 12 hours during the period of risk. For prevention of early reactivation in HCT recipients, initiate therapy beginning 1 day prior to transplant and continue until marrow engraftment. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.

    Infants, Children, and Adolescents

    5 mg/kg/dose IV every 8 hours during the period of risk. For prevention of early reactivation in HCT recipients, initiate therapy beginning 1 day prior to transplant and continue until marrow engraftment. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.

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

    800 mg PO 5 times daily for 5 to 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; however, this intervention has not been studied in patients with HIV. Post-exposure prophylaxis is indicated for persons with HIV who lack evidence of immunity to varicella with substantial exposure to a contact with varicella or herpes zoster.

    Adolescents

    800 mg PO 5 times daily for 5 to 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; however, this intervention has not been studied in patients with HIV. Post-exposure prophylaxis is indicated for persons with HIV who lack evidence of immunity to varicella with substantial exposure to a contact with varicella or herpes zoster.[34362]

    Infants and Children

    20 mg/kg/dose PO 4 times daily (Max: 800 mg/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 for acyclovir prophylaxis in patients with HIV, other experts consider it prudent to wait until rash appears to begin acyclovir treatment. Post-exposure prophylaxis is indicated for children with HIV who lack evidence of immunity to varicella with substantial exposure to a contact with varicella or herpes zoster. Some limit this recommendation to children who are severely immunocompromised (i.e., CDC Immunologic Category 3), particularly if also classified as CDC Clinical Category C and experiencing high HIV RNA plasma viral load.

    For cytomegalovirus (CMV) disease prophylaxis†.
    For prevention of CMV disease† in immunocompromised patients.
    Intravenous dosage
    Adults

    500 mg/m2/dose IV every 8 hours during the period of risk has been used. FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[28977]

    Children and Adolescents

    500 mg/m2/dose IV every 8 hours during the period of risk has been used. FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[28977] Similar consideration should be given to pediatric patients.

    For prevention of CMV disease† in CMV-seropositive patients receiving bone marrow transplantation.
    Intravenous dosage
    Adults

    500 mg/m2/dose IV every 8 hours. Prophylaxis with acyclovir has been shown to decrease the rate of CMV infection and improve survival in hematopoietic cell transplantation (HSCT) recipients. Acyclovir is considered an alternative to ganciclovir for prophylaxis of CMV infection in HSCT recipients. FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Children and Adolescents

    500 mg/m2/dose IV every 8 hours.[23936] [56888] [56889] [56898] Prophylaxis with acyclovir has been shown to decrease the rate of CMV infection and improve survival in hematopoietic cell transplantation (HSCT) recipients.[23936] [56888] [56889] Acyclovir is considered an alternative to ganciclovir for prophylaxis of CMV infection in HSCT recipients.[51812] FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[34408] Similar consideration should be given to pediatric patients.

    Oral dosage
    Adults

    800 mg PO 4 times per day as an alternative to ganciclovir for prophylaxis of CMV infection in hematopoietic cell transplantation recipients.

    Children and Adolescents weighing 40 kg or more

    800 mg PO 4 times per day as an alternative to ganciclovir for prophylaxis of CMV infection in hematopoietic cell transplantation recipients.

    Children and Adolescents weighing less than 40 kg

    600 mg/m2/dose PO 4 times per day as an alternative to ganciclovir for prophylaxis of CMV infection in hematopoietic cell transplantation recipients.

    For CMV disease prophylaxis† in adults receiving renal transplantation.
    Oral dosage
    Adults

    800 mg PO 6 hours prior to transplantation, followed by 800 mg PO 24 hours after transplantation, followed by 800 mg PO four times per day has been utilized. Dosage was adjusted for patients with compromised renal function. However, guidelines recommend prophylaxis with other agents, including valacyclovir, ganciclovir, and valganciclovir; use of acyclovir has been deemed inferior and, thus, fallen out of favor.

    For the treatment of hairy leukoplakia† in HIV-infected patients.
    Oral dosage
    Adults

    800 mg PO every 6 hours for 20 days was found effective in an open label study of a small number of HIV-positive men. After therapy was discontinued, recurrences developed in all 5 patients who had initially responded.

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

    400 mg PO 5 times daily for 10 days or 800 mg PO 3 times daily for 5 to 10 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 the treatment of herpes simplex ocular infection†, including herpes simplex virus epithelial keratitis†, herpes simplex virus stromal keratitis†, and herpes simplex virus endothelial keratitis†.
    NOTE: See neonatal herpes simplex virus infection for the treatment of herpes simplex ocular infection in neonates and young infants.
    For the treatment of dendritic epithelial keratitis.
    Oral dosage
    Adults

    400 mg PO 3 to 5 times daily for 7 to 10 days.

    Children and Adolescents 6 to 17 years

    400 mg PO 3 times daily for 7 to 10 days.

    Infants and Children 1 to 5 years

    20 to 80 mg/kg/day (Max: 1,200 mg/day) PO divided 3 times daily for 7 to 10 days.

    For the treatment of geographic epithelial keratitis.
    Oral dosage
    Adults

    800 mg PO 5 times daily for 14 to 21 days.

    Children and Adolescents 6 to 17 years

    400 mg PO 3 times daily for 14 to 21 days.

    Infants and Children 1 to 5 years

    20 to 80 mg/kg/day (Max: 1,200 mg/day) PO divided 3 times daily for 14 to 21 days.

    For the treatment of non-necrotizing stromal keratitis.
    NOTE: After acute treatment, long-term prophylaxis is recommended in pediatric patients due to the high rates of recurrence.  
    Oral dosage
    Adults

    400 mg PO twice daily plus topical ophthalmic steroid for at least 10 weeks.

    Children and Adolescents 6 to 17 years

    400 mg PO twice daily plus topical ophthalmic steroid for at least 10 weeks, then 400 mg PO twice daily as long-term prophylaxis.

    Infants and Children 1 to 5 years

    20 to 80 mg/kg/day (Max: 800 mg/day) PO divided twice daily plus topical ophthalmic steroid for at least 10 weeks, then 20 to 80 mg/kg/day (Max: 800 mg/day) PO divided twice daily as long-term prophylaxis.

    For the treatment of necrotizing stromal keratitis.
    NOTE: After acute treatment, long-term prophylaxis is recommended in pediatric patients due to the high rates of recurrence.  
    Oral dosage
    Adults

    800 mg PO 3 to 5 times daily for 7 to 10 days plus topical ophthalmic steroid, then 400 mg PO twice daily for the duration of topical ophthalmic steroid use.

    Children and Adolescents 6 to 17 years

    400 mg PO 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 400 mg PO twice daily as long-term prophylaxis.

    Infants and Children 1 to 5 years

    20 to 80 mg/kg/day (Max: 1,200 mg/day) PO divided 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 20 to 80 mg/kg/day (Max: 800 mg/day) PO divided twice daily as long-term prophylaxis.

    For the treatment of endothelial keratitis.
    Oral dosage
    Adults

    400 to 800 mg PO 3 to 5 times daily for 7 to 10 days plus topical ophthalmic steroid, then 400 mg PO twice daily for the duration of topical ophthalmic steroid use.

    Children and Adolescents 6 to 17 years

    400 mg PO 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 400 mg PO twice daily for the duration of topical ophthalmic steroid use.

    Infants and Children 1 to 5 years

    20 to 80 mg/kg/day (Max: 1,200 mg/day) PO divided 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 20 to 80 mg/kg/day (Max: 800 mg/day) PO divided twice daily for the duration of topical ophthalmic steroid use.

    For secondary herpes simplex ocular infection prophylaxis†.
    NOTE: Prophylaxis is indicated for multiple recurrences of any type of HSV keratitis, especially stromal keratitis.
    Oral dosage
    Adults

    400 mg PO twice daily for at least 12 months.

    Children and Adolescents 12 to 17 years

    400 mg PO twice daily for at least 12 months.

    Infants and Children 1 to 11 years

    20 to 80 mg/kg/day (Max: 800 mg/day) PO divided twice daily for at least 12 months.

    For the treatment of ocular infections [acute retinal necrosis (ARN)† and progressive outer retinal necrosis (PORN)†] due to varicella-zoster virus in persons living with HIV.
    For the treatment of acute retinal necrosis (ARN)†.
    Oral dosage
    Infants and Children

    After initial IV therapy, 20 mg/kg/dose PO 4 times daily for 4 to 6 weeks in patients unable to take valacyclovir.

    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours for 10 to 14 days plus intravitreal ganciclovir injection until evidence of treatment response, then oral valacyclovir for at least 14 weeks. Involvement of an experienced ophthalmologist is recommended. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Adolescents

    10 mg/kg/dose IV every 8 hours for 10 to 14 days plus intravitreal ganciclovir injection until evidence of treatment response, then oral valacyclovir for at least 14 weeks. Involvement of an experienced ophthalmologist is recommended. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.

    Infants and Children

    10 to 15 mg/kg/dose IV every 8 hours for 10 to 14 days followed by oral therapy with valacyclovir or acyclovir for 4 to 6 weeks. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.

    For the treatment of progressive outer retinal necrosis (PORN)†.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours plus ganciclovir intravitreal injection and/or foscarnet intravitreal injection. The duration of therapy is not well defined and should be based on clinical, virologic, and immunologic responses in consultation with ophthalmologist. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Adolescents

    10 mg/kg/dose IV every 8 hours plus ganciclovir intravitreal injection and/or foscarnet intravitreal injection. The duration of therapy is not well defined and should be based on clinical, virologic, and immunologic responses in consultation with ophthalmologist. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    Infants and Children

    10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours plus IV foscarnet plus ganciclovir intravitreal injection and/or foscarnet intravitreal injection. The duration of therapy is not well defined and should be based on clinical, virologic, and immunologic responses in consultation with an ophthalmologist. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    30 mg/kg/day IV per FDA-approved product labeling; however, up to 45 mg/kg/day IV is used off-label; 4,000 mg/day PO; 50 mg/dose buccal.

    Geriatric

    30 mg/kg/day IV per FDA-approved product labeling; however, up to 45 mg/kg/day IV is used off-label; 4,000 mg/day PO; 50 mg/dose buccal.

    Adolescents

    30 mg/kg/day IV per FDA-approved product labeling; however, up to 45 mg/kg/day IV is used off-label. 80 mg/kg/day PO (Max: 3,200 mg/day) per FDA-approved product labeling; however, 4,000 mg/day has been used off-label; safety and efficacy of buccal tablet not established.

    Children

    12 years: 30 mg/kg/day IV per FDA-approved product labeling; however, up to 45 mg/kg/day IV is used off-label; 80 mg/kg/day PO (Max: 3,200 mg/day) per FDA-approved product labeling; however, 4,000 mg/day has been used off-label; safety and efficacy of buccal tablet not established.
    2 to 11 years: 60 mg/kg/day IV; 80 mg/kg/day PO (Max: 3,200 mg/day); safety and efficacy of buccal tablet not established.
    1 year: 60 mg/kg/day IV; safety and efficacy of oral acyclovir have not been established; however, 80 mg/kg/day PO has been used off-label.

    Infants

    60 mg/kg/day IV; safety and efficacy of oral acyclovir have not been established; however, 80 mg/kg/day PO has been used off-label.

    Neonates

    60 mg/kg/day IV; safety and efficacy of oral acyclovir have not been established; however, 900 mg/m2/day PO has been used off-label for suppressive therapy of neonatal herpes.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment needed.

    Renal Impairment

    Non-neonatal Populations
    CrCl more than 50 mL/min/1.73 m2: no dosage adjustment needed.
    CrCl 26 to 50 mL/min/1.73 m2: extend IV dosing interval to every 12 hours. No adjustment required for oral dosage regimens.
    CrCl 11 to 25 mL/min/1.73 m2: extend IV dosing interval to every 24 hours. For patients receiving 800 mg PO 5 times per day, the dosage interval should be extended to every 8 hours. No dosage adjustment is necessary for patients receiving 400 mg PO every 12 hours or 200 mg PO 5 times per day.
    CrCl 10 mL/min/1.73 m2 or less: reduce recommended IV dose by 50% and extend dosing interval to every 24 hours. For patients receiving 800 mg PO 5 times per day, reduce dose to 800 mg PO every 12 hours. For patients receiving or 400 mg PO every 12 hours or 200 mg PO 5 times per day, reduce dose to 200 mg PO every 12 hours.
     
    Neonates
    CrCl more than 50 mL/min/1.73 m2 or serum creatinine less than 0.7 mg/dL: no dosage adjustment needed.
    CrCl 25 to 50 mL/min/1.73 m2 or serum creatinine 0.8 to 1.1 mg/dL: extend IV dosing interval to every 12 hours.
    CrCl 10 to 24 mL/min/1.73 m2 or serum creatinine 1.2 to 1.5 mg/dL: extend IV dosing interval to every 24 hours.
    CrCl less than 10 mL/min/1.73 m2, serum creatinine more than 1.5 mg/dL, or urine output less than 1 mL/kg/hr: reduce recommended IV dose by 50% and extend dosing interval to every 24 hours.
     
    Intermittent hemodialysis
    For IV dosing, 2.5 to 5 mg/kg/dose IV every 24 hours (based on usual dose of 5 to 10 mg/kg/dose IV every 8 hours, and the assumption of 3 complete hemodialysis sessions/week). Adjust the dosing schedule so that a dose is administered after each dialysis session. For oral dosing, see dosage based on creatinine clearance and adjust the schedule so that a dose is administered after each dialysis session.
     
    Continuous renal replacement therapy (CRRT)
    Acyclovir is removed by CRRT; however, clearance is significantly affected by the type of renal replacement therapy, filter type, and flow rate. For CVVH, a dose of 5 to 10 mg/kg/dose IV every 24 hours has been recommended. For CVVHD and CVHDF, a dose of 5 to 10 mg/kg/dose IV every 12 to 24 hours has been recommended. Another recommendation in pediatric patients is 10 mg/kg/dose IV every 12 hours, although method of CRRT is not specified. These are general recommendations only and therapy should be individualized based on therapeutic drug monitoring; some patients may require higher doses to optimize therapy.
     
    Peritoneal dialysis
    For IV dosing, 5 mg/kg/dose IV every 24 hours. Supplemental systemic doses do not appear to be necessary after peritoneal dialysis.
     
    PlasmapheresisAdminister IV doses at least 3 hours before plasmapheresis.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Solid Formulations

    Buccal tablet:
    With a dry finger, remove the tablet out of the blister. 
    On the same side of the mouth as the herpes labialis symptoms, immediately apply the rounded side of the tablet to the upper gum above the incisor tooth (canine fossa). Hold the tablet in place with slight pressure for 30 seconds.
    Once adhered, the tablet will gradually dissolve. Do not crush, chew, suck, or swallow the tablet.
    If adhesion does not occur or the tablet falls off within the first 6 hours, immediately reposition the same tablet. If the tablet cannot be repositioned, a new tablet should be applied.
    If the tablet is swallowed within the first 6 hours, instruct the patient to drink a glass of water and apply a new tablet.
    If the tablet falls or is swallowed after the first 6 hours, reapplication is not needed.

    Oral Liquid Formulations

    Shake the suspension well prior to administration. Measure the suspension with a calibrated oral dosing device to give accurate dosage.[28977]

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution
    Reconstitute 500 mg or 1 g vial with 10 or 20 mL, respectively, of sterile water for injection (preservative-free) to give a concentration of 50 mg/mL. Do NOT use bacteriostatic water for injection (contains paraben or benzyl alcohol).
    Further dilution is required prior to administration.
    Storage: Use reconstituted solutions within 12 hours. Do NOT refrigerate. Refrigeration may result in the formation of a precipitate, which will re-dissolve at room temperature.[34408]
     
    Dilution
    Withdraw appropriate dose of reconstituted solution and dilute with a compatible IV infusion solution (refer to the manufacturer's guidance for specific compatible solutions).[34408]
    Final concentrations for infusion should be 7 mg/mL or less. Higher concentrations (e.g., 10 mg/mL) are associated with phlebitis or injection site reactions.[34408]
    Institute for Safe Medication Practices (ISMP)/Vermont Oxford Network (VON) Recommended Standard Concentration for Neonatal Administration: 7 mg/mL [51889]
    Storage: Once appropriately diluted, administer the dose within 24 hours. Store the diluted infusion solution at room temperature, 15 to 25 degrees C (59 to 77 degrees F). If refrigerated, a precipitate may form, which will dissolve once warmed to room temperature.[34408]
     
    Intermittent IV Infusion
    Infuse slowly IV over at least 1 hour to minimize the risk of adverse reactions.
    Monitor IV site for signs of phlebitis.[34408]

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Do not apply the topical ointment or cream to the eye.
    Use a finger cot or rubber glove when applying to avoid transmission of the virus to other sites or persons.
    Wash hands thoroughly after administration.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sitavig:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zovirax:
    - Store between 68 to 77 degrees F
    Zovirax Cream:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zovirax Ointment:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place
    Zovirax Powder:
    - Store between 59 to 77 degrees F
    Zovirax Suspension:
    - Protect from light
    - Store between 59 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

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

    Acyclovir is contraindicated in patients who have developed acyclovir hypersensitivity or valacyclovir hypersensitivity. The acyclovir buccal tablet is contraindicated in patients with milk protein hypersensitivity. Because of similar chemical structures and possible cross-sensitivity, acyclovir should not be used 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.

    Dehydration, renal failure, renal impairment

    Since acyclovir is excreted primarily by glomerular filtration and tubular secretion, use caution when administering systemic acyclovir to patients with renal dysfunction. Patients with renal impairment or renal failure should receive lower doses of acyclovir at longer intervals. Patients with renal dysfunction are at increased risk of acyclovir-induced neurotoxicity due to high levels of acyclovir. In order to prevent crystalluria, patients should be well-hydrated to maintain a high urine volume and avoid dehydration during therapy with acyclovir. Patients receiving potentially nephrotoxic drugs together with acyclovir may have an increased risk of renal dysfunction. Additionally, intravenous acyclovir must be administered over 1 hour to avoid the precipitation of acyclovir crystals in the renal tubules which could result in damage and acute renal failure.

    Electrolyte imbalance, hepatic disease, hypoxemia, neurological disease, seizure disorder

    Encephalopathic changes have been associated with systemic acyclovir use. Use acyclovir with caution in patients with a preexisting seizure disorder, other neurological disease, electrolyte imbalance, significant hypoxemia, or significant renal or hepatic disease due to a possible increased risk of adverse effects.

    Geriatric

    For systemic acyclovir, the duration of pain after healing was longer in geriatric patients 65 years and older compared to younger patients. Renal adverse events, nausea, vomiting, and dizziness are more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have CNS adverse events (e.g., somnolence, hallucinations, confusion, or coma) possibly related to changes in renal function.

    Pregnancy

    No adequate or well-controlled studies have been conducted to evaluate use of acyclovir during human pregnancy; however, published observational studies over decades of acyclovir use have not identified a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. Further, a prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. 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. Acyclovir was not found to be teratogenic in standard animal studies. Avoid use of systemic acyclovir during pregnancy unless the potential benefits outweigh the possible risks to the fetus.[28977] [41766] [43519] [54268] Acyclovir is minimally absorbed systemically following topical use. Maternal use is not expected to result in fetal exposure to acyclovir topical cream.

    Breast-feeding

    There are no data on the effects of systemic acyclovir on the breastfed child or on milk production. Following oral administration of acyclovir, breast milk concentrations 1- to 4-times that of those found in maternal plasma have been observed.[24464] These concentrations would potentially expose the nursing infant to a dose of acyclovir as high as 0.3 mg/kg/day. Intravenous acyclovir doses of 60 mg/kg/day are used for the treatment of neonatal herpes, and the American Academy of Pediatrics has considered the maternal use of systemic acyclovir to be compatible with breast-feeding.[27500] Although there are no data on the presence of acyclovir in human milk following buccal administration, this route produces low systemic drug exposures. Acyclovir cream is minimally absorbed systemically following topical use, and breast-feeding is not expected to result in exposure of the breastfed child to acyclovir topical cream. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for acyclovir cream and any potential adverse effects on the breastfed child or from the underlying maternal condition.

    Children, infants, neonates

    Use of the buccal tablet should be avoided in neonates, infants, and young children because of its complex administration procedure and the potential risk of choking.[54268]

    Ophthalmic administration

    Acyclovir cream and ointment products are for external topical use only; avoid ophthalmic administration or use inside the mouth or nose.

    Extravasation, intramuscular administration, subcutaneous administration

    Acyclovir for injection is intended for intravenous use only. It is not for intramuscular administration or subcutaneous administration. Extravasation may cause phlebitis and inflammation of surrounding tissues.

    Obesity

    Acyclovir dosage should be based on ideal body weight in patients with obesity. Several case reports describe acyclovir-induced nephrotoxicity and neurotoxicity in obese patients who were given large doses of acyclovir based on actual rather than ideal body weight. Acyclovir is minimally lipophilic and distributes primarily to extracellular fluid.

    Immunosuppression

    Systemic acyclovir has been associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, in immunocompromised patients. Monitor patients receiving immunosuppression carefully while on acyclovir therapy.[28977] [34408] Acyclovir cream is indicated for immunocompetent patients only; efficacy has not been established for immunocompromised patients.[43519]

    ADVERSE REACTIONS

    Severe

    coma / Early / 1.0-1.0
    seizures / Delayed / 1.0-1.0
    renal tubular obstruction / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known

    Moderate

    phlebitis / Rapid / 9.0-9.0
    elevated hepatic enzymes / Delayed / 1.0-2.0
    hallucinations / Early / 1.0-1.0
    confusion / Early / 1.0-1.0
    encephalopathy / Delayed / 1.0-1.0
    erythema / Early / 1.0-1.0
    anemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    thrombocytosis / Delayed / 0-1.0
    stomatitis / Delayed / 1.0-1.0
    crystalluria / Delayed / Incidence not known
    delirium / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hemolysis / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known

    Mild

    skin irritation / Early / 1.0-30.0
    malaise / Early / 11.5-11.5
    injection site reaction / Rapid / 9.0-9.0
    nausea / Early / 2.4-7.0
    vomiting / Early / 2.7-7.0
    pruritus / Rapid / 1.0-4.0
    diarrhea / Early / 2.4-3.2
    headache / Early / 2.2-3.0
    rash / Early / 1.0-2.0
    lethargy / Early / 1.0-1.0
    tremor / Early / 1.0-1.0
    dizziness / Early / 1.0-1.0
    agitation / Early / 1.0-1.0
    leukocytosis / Delayed / 0-1.0
    drowsiness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    fever / Early / Incidence not known
    myalgia / Early / Incidence not known

    DRUG INTERACTIONS

    Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as acyclovir, 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 acyclovir, 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.
    Amikacin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Aminoglycosides: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Concurrent use of amphotericin B and other nephrotoxic medications, including acyclovir, 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 acyclovir, 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 acyclovir, 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 acyclovir, 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 acyclovir, as the risk of renal impairment may be increased.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including acyclovir, 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.
    Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as acyclovir, is contraindicated. Acyclovir 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 acyclovir is necessary. Cisplatin can cause nephrotoxicity. Acyclovir can cause renal impairment or renal failure, which may be additive when used with cisplatin.
    Clindamycin: (Moderate) Concomitant use of acyclovir and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
    Clofarabine: (Moderate) Concomitant use of clofarabine and acyclovir may result in altered clofarabine levels because both agents are substrates of OAT1 and OCT1. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OAT1 and OCT1 substrates.
    Colistin: (Moderate) Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including acyclovir, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Cyclosporine: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as acyclovir. Monitor renal function and fluid status carefully.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    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 acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. 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 acyclovir. 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 acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. 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 acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. 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 acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for acyclovir or emtricitabine-related adverse events during concomitant use. Concomitant use may increase acyclovir or emtricitabine concentrations. Coadministration of drugs that reduce renal function or compete for active tubular secretion, such as acyclovir and emtricitabine, may increase the risk of adverse reactions. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. 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) Because entecavir is primarily eliminated by the kidneys and acyclovir can affect renal function, concurrent administration with acyclovir may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Ethiodized Oil: (Moderate) Concomitant use of acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Ethotoin: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
    Foscarnet: (Major) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents, such as acyclovir. Avoid concurrent use, unless the potential benefits outweigh the risks to the patient.
    Fosphenytoin: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
    Gentamicin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    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 acyclovir. Administer IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential risk for developing acute renal failure.
    Hydantoins: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
    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 acyclovir. Administer IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential risk for developing acute renal failure.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and acyclovir due to the risk of glomerulonephritis and nephrotoxicity.
    Iodipamide Meglumine: (Moderate) Concomitant use of acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Iodixanol: (Moderate) Concomitant use of acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Iohexol: (Moderate) Concomitant use of acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Iomeprol: (Moderate) Concomitant use of acyclovir 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 acyclovir 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 acyclovir 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 acyclovir 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 acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Ioxaglate Meglumine; Ioxaglate Sodium: (Moderate) Concomitant use of acyclovir 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 acyclovir and contrast agents should be avoided when possible, as use of these drugs together may increase the risk for nephrotoxicity.
    Kanamycin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    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 acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Lithium: (Moderate) Consider starting with a lower lithium dose and monitor lithium concentrations and for signs and symptoms of lithium toxicity during concomitant acyclovir use. The risk of lithium toxicity is increased with concomitant use of medications that affect kidney function, such as acyclovir.
    Mannitol: (Major) Avoid use of mannitol and acyclovir, if possible. Concomitant administration of nephrotoxic drugs, such as acyclovir, increases the risk of renal failure after administration of mannitol.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) If possible, discontinue acyclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. In patients with HIV, guidelines recommend waiting at least 72 hours after the last dose of acyclovir before administering varicella vaccines. Also, do not administer acyclovir 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. Acyclovir 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) Avoid concomitant use of methotrexate with acyclovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Acyclovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with acyclovir may result in decreased renal function as well as increased methotrexate plasma concentrations.
    Mycophenolate: (Moderate) Coadministration of mycophenolate mofetil and acyclovir to healthy volunteers resulted in no significant change in mycophenolic acid concentrations or AUC. However, the glucuronide metabolite of mycophenolate (MPAG) and acyclovir AUCs were increased 10.6% and 21.9%, respectively. Because MPAG and acyclovir concentrations are increased in the presence of renal impairment, the potential exists for the two drugs to compete for tubular secretion, further increasing the concentration of both drugs in patients renal dysfunction.
    Non-Ionic Contrast Media: (Moderate) Concomitant use of acyclovir 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 acyclovir and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
    Paromomycin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Phenytoin: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
    Plazomicin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Probenecid: (Moderate) Probenecid decreases the renal tubular secretion of acyclovir and can increase serum and CSF concentrations of acyclovir, increasing the potential for toxicity. This interaction would appear to be more significant for parenteral acyclovir.
    Probenecid; Colchicine: (Moderate) Probenecid decreases the renal tubular secretion of acyclovir and can increase serum and CSF concentrations of acyclovir, increasing the potential for toxicity. This interaction would appear to be more significant for parenteral acyclovir.
    Streptomycin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    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 acyclovir. 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.
    Telavancin: (Moderate) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as acyclovir may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Telbivudine: (Moderate) Drugs that alter renal function such as acyclovir 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 renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
    Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. 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.
    Theophylline, Aminophylline: (Minor) Caution is advised when administering theophylline, aminophylline with acyclovir. Theophylline is primarily metabolized by CYP1A2; acyclovir is a weak inhibitor of CYP1A2. Taking these drugs together may increase the serum concentration of theophylline. Since the therapeutic range of theophylline is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2.
    Tizanidine: (Minor) Caution is advised when administering tizanidine with acyclovir. Tizanidine is primarily metabolized by CYP1A2; acyclovir is a weak inhibitor of CYP1A2. Taking these drugs together may increase the serum concentration of tizanidine, which could result in hypotension, bradycardia, or excessive drowsiness.
    Tobramycin: (Moderate) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Vancomycin: (Moderate) Closely monitor renal function if concomitant use with acyclovir 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 acyclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. In patients with HIV, guidelines recommend waiting at least 72 hours after the last dose of acyclovir before administering varicella vaccines. Also, do not administer acyclovir 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. Acyclovir has a relatively short serum half-life and is quickly cleared from the body. Refer to the most recent Center for Disease control guidance if concurrent use is necessary.
    Voclosporin: (Moderate) Concomitant use of voclosporin and acyclovir may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate or well-controlled studies have been conducted to evaluate use of acyclovir during human pregnancy; however, published observational studies over decades of acyclovir use have not identified a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. Further, a prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. 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. Acyclovir was not found to be teratogenic in standard animal studies. Avoid use of systemic acyclovir during pregnancy unless the potential benefits outweigh the possible risks to the fetus.[28977] [41766] [43519] [54268] Acyclovir is minimally absorbed systemically following topical use. Maternal use is not expected to result in fetal exposure to acyclovir topical cream.

    There are no data on the effects of systemic acyclovir on the breastfed child or on milk production. Following oral administration of acyclovir, breast milk concentrations 1- to 4-times that of those found in maternal plasma have been observed.[24464] These concentrations would potentially expose the nursing infant to a dose of acyclovir as high as 0.3 mg/kg/day. Intravenous acyclovir doses of 60 mg/kg/day are used for the treatment of neonatal herpes, and the American Academy of Pediatrics has considered the maternal use of systemic acyclovir to be compatible with breast-feeding.[27500] Although there are no data on the presence of acyclovir in human milk following buccal administration, this route produces low systemic drug exposures. Acyclovir cream is minimally absorbed systemically following topical use, and breast-feeding is not expected to result in exposure of the breastfed child to acyclovir topical cream. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for acyclovir cream and any potential adverse effects on the breastfed child or from the underlying maternal condition.

    MECHANISM OF ACTION

    Acyclovir is a synthetic purine deoxynucleoside 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.[28977] [34408] [54268] [63157]
     
    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]
     
    Resistance to acyclovir by herpes virus results from mutations in viral thymidine kinase and DNA polymerase that cause a loss of thymidine kinase activity, alterations in thymidine kinase (TK) substrate specificity, or decreased DNA polymerase sensitivity. The most common mechanism of resistance is loss of TK activity. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). These viral variants are also cross resistant to other antiviral agents (e.g., foscarnet, famciclovir, and penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in infants and 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.[28977] [34408] [54268] [63157] [54905]

    PHARMACOKINETICS

    Acyclovir is administered topically, ophthalmically, orally, buccally, and intravenously. Acyclovir distributes extensively into all tissues, with the highest concentrations in the kidneys, liver, and intestines; acyclovir crosses the placenta. Cerebrospinal fluid (CSF) concentrations are approximately 50% of plasma concentrations.[51529] Acyclovir is poorly protein bound at 9% to 33%; protein binding is independent of plasma acyclovir concentrations.[51536] Excretion is via glomerular filtration and tubular secretion, with approximately 62% to 91% of the drug excreted unchanged.[34408] The only known urinary metabolite is 9-[(carboxy-methoxy)methyl]guanine, which accounts for 8.5% to 14% of the dose in patients with normal renal function. Probenecid decreases acyclovir renal clearance by approximately 32%, presumably by inhibiting tubular secretion of acyclovir.[51529] The elimination half-life of acyclovir in patients with normal renal function is 2.5 to 3.3 hours.[28977] [34408]
     
    Affected cytochrome P450 isoenzymes: CYP1A2
    Acyclovir is a weak inhibitor of the CYP1A2 isoenzyme. Data on clinical interactions resulting from CYP1A2 inhibition by acyclovir are limited.[56579] [61130]

    Oral Route

    Acyclovir is poorly absorbed from the GI tract, with an oral bioavailability of 10% to 20%. As the administered dose increases, the bioavailability decreases, resulting in less than dose proportional increase in acyclovir concentrations (e.g., 200 mg Cmax, 0.83 mcg/mL; 400 mg Cmax, 1.21 mcg/mL; 800 mg Cmax, 1.61 mcg/mL). Of note, the decrease in bioavailability is a function of the dose and not the dosage form. Food does not affect the absorption of acyclovir.[28977]

    Intravenous Route

    Mean peak acyclovir plasma concentrations have been shown to be directly proportional to the dose administered. After intravenous administration of acyclovir, the mean Cmax in adult patients is 9.8 mcg/mL with 5 mg/kg/dose every 8 hours and 22.9 mcg/mL with 10 mg/kg/dose every 8 hours.

    Topical Route

    After administration of the topical ointment, 30% to 50% of the drug reaches the basal epidermis in cutaneous infections.[51536] Data suggests systemic absorption of acyclovir after topical application is minimal. Percutaneous absorption of acyclovir 5% ointment was evaluated in 2 clinical pharmacology studies. In the first study, patients were administered a 1-cm strip (25 mg acyclovir) dose 4-times daily for 7 days to an intact skin surface area of 4.5 square inches. After 7 days, a radioimmunoassay (sensitivity, 0.01 mcg/mL) failed to detect any drug in the blood or urine of these patients. In the second study, absorption of acyclovir ointment was evaluated in 11 patients with localized varicella-zoster infections. In this study, acyclovir was identified in the urine of all 11 patients, and in the blood of 9 patients. More specifically, in 8 patients with normal renal function the drug plasma concentrations ranged from less than 0.01 to 0.28 mcg/mL; in 1 patient with impaired renal function, drug concentrations ranged from less than 0.01 to 0.78 mcg/mL. Acyclovir excretion in the urine ranged from less than 0.02% to 9.4% of the daily dose.[51547]

    Other Route(s)

    Buccal Route
    Buccal administration of a single 50 mg acyclovir dose achieves a mean maximum salivary concentration (Cmax) of 440 +/- 241 mcg/mL approximately 7 hours after application of the tablet, with concentrations declining to 88.1 mcg/mL after 24 hours. Acyclovir concentrations in the plasma are delayed (undetectable at 5 hours) and do not reach levels required for antiviral activity (range: 17.5 to 55.3 ng/mL). The tablet remains adhered for a median duration of 14 hours and, although the effects of food have not been formally studied, patients were allowed to eat and drink during clinical studies.[54268]