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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).
    Available as oral, buccal, parenteral, topical, and ophthalmic formulations

    COMMON BRAND NAMES

    Sitavig, Zovirax

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of neonatal herpes simplex virus infection.
    Intravenous dosage
    Infants 1 to 4 months

    20 mg/kg/dose IV every 8 hours. For infants with HSV infection but who have not progressed to HSV disease, treat for 10 days to prevent progression from infection to disease (preemptive therapy). For localized disease, treat for 14 days. For CNS or disseminated disease, treat for at least 21 days. 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 IV 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.[34213] [34408] [54855] [63245] For neonates with HSV infection but who have not progressed to HSV disease, treat for 10 days to prevent progression from infection to disease (preemptive therapy). For localized disease, treat for 14 days. For CNS or disseminated disease, treat for at least 21 days.[34213] [63245] 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 IV 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.[54855]

    Neonates younger than 34 weeks postmenstrual age

    20 mg/kg/dose IV every 12 hours. For neonates with HSV infection but who have not progressed to HSV disease, treat for 10 days to prevent progression from infection to disease (preemptive therapy). For localized disease, treat for 14 days. For CNS or disseminated disease, treat for at least 21 days. 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 IV 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.
    For 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] [59799] The FDA-approved labeling recommends a duration of 10 days; however, relapses have occurred with 10-day treatment courses.[34213] [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

    10 mg/kg/dose IV every 8 hours for 14 to 21 days.[34213] [59799] [63245] The FDA-approved labeling recommends a duration of 10 days; however, relapses have occurred with 10-day treatment courses.[34213] [34408] In HIV-infected patients, guidelines recommend treatment for 21 days.[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 3 months to 11 years

    10 to 15 mg/kg/dose IV every 8 hours for 14 to 21 days.[34213] [63245] A dose of 500 mg/m2/dose IV every 8 hours for 10 to 14 days has also been recommended.[24642] While 20 mg/kg/dose IV every 8 hours for 10 days is the FDA-approved regimen, a longer treatment regimen is recommended because relapse of herpes simplex encephalitis has been reported after only 10 days of therapy.[34213] [34408] [63245] In HIV-infected patients, guidelines recommend treatment for 21 days.[34361] The lower dose (10 to 15 mg/kg/dose) is recommended by the American Academy of Pediatrics (AAP) due to increased risk of nephrotoxicity with 20 mg/kg/dose.[63245] 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†

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

    For varicella-zoster encephalitis†.
    Intravenous dosage
    Adults

    10 to 15 mg/kg/dose IV every 8 hours for 10 to 14 days is recommended by the IDSA on the basis of case reports and case series.[34213] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408]

    For 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 is recommended by the IDSA on the basis of case reports.[34213] The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408]

    For the treatment of herpes labialis (i.e., cold sores) or herpes fibrilis caused by herpes simplex virus.
    For the treatment of recurrent herpes labialis in immunocompetent adults.
    Buccal dosage
    Adults

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

    Oral dosage†
    Adults

    400 mg PO 3 times per day for 5 to 10 days is recommended by guidelines for HIV-infected patients.[34362]

    Adolescents

    20 mg/kg/dose PO given 4 times daily (Max: 3,200 mg/day) for 5 to 7 days is recommended by the American Academy of Pediatrics (AAP) based on limited data.[63245] For HIV-infected patients, guidelines recommend 400 mg PO 3 times daily for 5 to 10 days.[34362]

    Infants and Children

    20 mg/kg/dose PO given 4 times daily (Max: 3,200 mg/day) for 5 to 7 days is recommended by the American Academy of Pediatrics (AAP) based on limited data.[63245] For HIV-infected patients, guidelines recommend 20 mg/kg/dose PO 4 times daily (Max: 400 mg/dose) for 7 to 10 days for mild symptomatic gingivostomatitis. For recurrent herpes labialis in HIV-infected patients, treat with the same dose for 5 days.[34361]

    Intravenous dosage
    Adults

    5 mg/kg/dose IV every 8 hours for 7 days is recommended in the FDA-approved labeling for immunocompromised patients; dosing for immunocompetent patients is not available. 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 is recommended in the FDA-approved labeling for immunocompromised patients; dosing for immunocompetent patients is not available. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] Once lesions begin to regress, a change to oral dosing is recommended.[34362]

    Infants and Children 1 to 11 years

    10 mg/kg/dose IV every 8 hours for 7 days is recommended in the FDA-approved labeling for immunocompromised patients; dosing for immunocompetent patients is not available. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.[34408] In HIV-infected patients, guidelines recommend 5 to 10 mg/kg/dose IV every 8 hours for moderate to severe symptomatic gingivostomatitis. Once lesions begin to regress, a change to oral dosing is recommended.[34361]

    Topical dosage (Ointment)
    Adults

    Apply sufficient quantity of ointment to adequately cover all lesions every 3 hours, 6 times a day for 7 days; initiate at the first sign of symptoms or lesions. 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.

    Topical dosage (Cream)
    Adults

    Apply sufficient quantity of cream to cover the lesions 5 times per day for 4 days. Initiate therapy as early as possible after onset of signs and symptoms (during the prodrome or when lesions appear). For immunocompetent patients only; efficacy has not been evaluated for immunocompromised patients.[43519]

    Children and Adolescents 12 to 17 years

    Apply sufficient quantity of cream to cover the lesions 5 times per day for 4 days. Initiate therapy as early as possible after onset of signs and symptoms (during the prodrome or when lesions appear). For immunocompetent patients only; efficacy has not been evaluated for immunocompromised patients.[43519]

    For the treatment of herpes zoster (shingles) infection.
    NOTE: For CNS infections, see encephalitis.
    For the treatment of herpes zoster (shingles) infection in bone marrow and organ transplant patients, patients receiving chemotherapy, and other immunocompromised patients.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours for 7 days.[34408] In HIV-infected patients with 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] [63245] For HIV-infected patients with trigeminal nerve involvement or extensive multi-dermatomal zoster, guidelines recommend treating with 10 to 15 mg/kg/dose IV every 8 hours until clinical improvement then 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.

    Infants and Children 1 to 11 years

    10 mg/kg/dose IV every 8 hours for 7 to 10 days is recommended by the American Academy of Pediatrics (AAP).[63245] The FDA-approved dosage regimen is 20 mg/kg/dose IV every 8 hours for 7 to 10 days.[34408] For HIV-infected patients with 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 every 4 hours, 5 times a day for 7 to 10 days.[28977] For HIV-infected patients with localized lesions, 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 HIV-infected patients, 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 per day for 7 to 10 days is recommended as an alternative therapy by guidelines for those with uncomplicated disease. Consider longer duration if lesions are slow to resolve. For extensive cutaneous lesions or visceral involvement in HIV-infected patients, 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 PO 4 times per day (Max: 800 mg/dose) for 7 to 10 days is recommended by guidelines for children with uncomplicated disease.[34361]

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

    800 mg PO every 4 hours, 5 times a day 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. A meta-analysis including 30 clinical trials of the treatment of herpes zoster determined that treatment with acyclovir 800 mg/day PO within 72 hours of rash onset may reduce the incidence of residual pain at 6 months by 46% in immunocompetent adults.

    Children and Adolescents 12 to 17 years†

    800 mg PO every 4 hours given 5 times per day for 5 to 7 days.[63245]

    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.[63245] 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 per day 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 PO 4 times per day (Max: 800 mg/dose) for 5 days.[28977] [63245] 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.[63245]

    Intravenous dosage†

    NOTE: Intravenous acyclovir is recommended for those with severe infection requiring hospitalization, including pregnant patients.[63245]

    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.[63245] 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. Guidelines recommend that HIV-infected patients with severe or complicated disease 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.[34362] [63245] Guidelines recommend that HIV-infected patients with severe or complicated disease 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.[34361] [63245] For patients with HIV, treat for 7 to 10 days or 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. For patients with HIV, treat for 7 to 10 days or 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 4 times daily for 5 days.[28977] In HIV-infected patients with uncomplicated disease, guidelines recommend 800 mg PO 5 times daily for 5 to 7 days as an alternative. 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]

    Adolescents

    800 mg PO 4 times daily for 5 days.[28977] In HIV-infected patients with uncomplicated disease, guidelines recommend 800 mg PO 5 times daily for 5 to 7 days as an alternative. 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]

    Children 2 to 12 years

    20 mg/kg/dose PO 4 times per day (Max: 800 mg/dose) for 5 days.[28977] For patients 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. Guidelines recommend treatment for 7 to 10 days or until there are no new lesions for 48 hours.[34361]

    Infants† and Children younger than 2 years†

    20 mg/kg/dose PO 4 times per day for 7 to 10 days. For patients 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. Guidelines recommend treatment for 7 to 10 days or until there are no new lesions for 48 hours.[34361]

    For the treatment of herpes genitalis caused by herpes simplex virus.
    For the treatment of initial herpes genitalis infection.
    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 to 7 days.[34408] [63245] The FDA-approved labeling recommends using ideal body weight when dosing obese adults.[34408] Similar considerations should be given to pediatric patients.

    Oral dosage
    Adults

    200 mg PO every 4 hours, 5 times per day for 10 days is the FDA-approved dosage.[28977] Guidelines recommend 400 mg PO 3 times per day or 200 mg PO 5 times per day for 7 to 10 days in immunocompetent patients and 400 mg PO 3 times per day for 5 to 10 days in HIV-infected patients.[34362] [59799]

    Children and Adolescents 12 to 17 years†

    400 mg PO 3 times per day or 200 mg PO 5 times per day for 7 to 10 days in immunocompetent patients. The duration of therapy may be extended if healing is incomplete by day 10. For HIV-infected patients, guidelines recommend 400 mg PO 3 times per day for 5 to 10 days.

    Infants† and Children 1 to 11 years†

    40 to 80 mg/kg/day PO in 3 to 4 divided doses (Max: 1,000 mg/day) for 7 to 10 days; treatment may be extended if healing is incomplete after 10 days.

    Topical dosage (Ointment)
    Adults

    Apply sufficient quantity of ointment to adequately cover all lesions every 3 hours, 6 times a day 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. Therapy should be initiated as early as possible after sign and symptom onset. There is no clinical benefit of the ointment in immunocompetent patients, although decreased viral shedding may be noted.

    For the treatment of recurrent herpes genitalis.
    Oral dosage
    Adults

    200 mg PO every 4 hours, 5 times a day for 5 days, initiated at the first sign or symptom or recurrence is the FDA-approved dosage. Guidelines recommend 400 mg PO 3 times per day for 5 days; 800 mg PO 3 times per day for 2 days; or 800 mg PO twice daily for 5 days, initiated at the first sign of prodrome or genital lesions. For HIV-infected patients, 400 mg PO 3 times per day for 5 to 10 days is recommended.

    Children and Adolescents 12 to 17 years†

    200 mg PO 5 times per day for 5 days; 400 mg PO 3 times per day for 5 days; 800 mg PO 3 times per day for 2 days; or 800 mg PO twice daily for 5 days, initiated at the first sign of prodrome or genital lesions. For HIV-infected patients, guidelines recommend 400 mg PO 3 times per day for 5 to 10 days.

    For chronic suppression therapy of recurrent herpes genitalis (i.e., herpes genitalis prophylaxis).
    Oral dosage
    Adults

    400 mg PO twice daily is recommended for patients with severe or frequent recurrences. Suppressive therapy is also recommended for HIV-infected patients who are initiating antiretroviral therapy and have a CD4 count less than 250 cells/mm3. In these patients, acyclovir reduces the risk for genital ulcer disease by 60% when compared to placebo. Alternative regimens have ranged from 200 mg PO 3 times daily to 200 mg PO 5 times daily. Suppressive therapy may be continued indefinitely; however, the decision to continue therapy should be reevaluated every year.

    Adolescents

    400 mg PO twice daily is recommended for patients with severe or frequent recurrences. Suppressive therapy is also recommended for HIV-infected patients who are initiating antiretroviral therapy and have a CD4 count less than 250 cells/mm3. In these patients, acyclovir reduces the risk for genital ulcer disease by 60% when compared to placebo.[34362] [59799] Alternative regimens have ranged from 200 mg PO 3 times daily to 200 mg PO 5 times daily.[28977] Suppressive therapy may be continued indefinitely; however, the decision to continue therapy should be reevaluated every year.[34362] [59799]

    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.
    Intravenous dosage
    Adults

    5 mg/kg/dose IV every 8 hours for 7 days is the FDA-approved dosage.[34408] The CDC recommends 5 to 10 mg/kg/dose IV every 8 hours for 2 to 7 days or until clinical improvement, then oral antiviral therapy to complete at least 10 days of total therapy. In HIV-infected patients, 5 to 10 mg/kg/dose IV every 8 hours is recommended by guidelines for severe mucocutaneous infections; switch to oral therapy after lesions regress and continue therapy until lesions have completely healed.[34362] [59799] For tracheobronchitis, a dose of 8 mg/kg/dose IV every 8 hours for 7 to 10 days has been used.[25114] 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 14 days is recommended by the American Academy of Pediatrics (AAP).[63245] In HIV-infected patients with disseminated disease, treat for 21 days.[34361] The FDA-approved dosage is 5 mg/kg/dose IV every 8 hours for 7 days for immunocompromised patients. The use of ideal body weight is recommended 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 7 to 14 days is recommended by the American Academy of Pediatrics (AAP).[63245] The FDA-approved labeling recommends 7 days of therapy for immunocompromised patients.[34408] In HIV-infected patients with disseminated disease, 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 7 to 14 days is recommended by the American Academy of Pediatrics (AAP).[63245] In HIV-infected patients with disseminated disease, 10 to 15 mg/kg/dose IV every 8 hours for 21 days is recommended.[34361]

    Oral dosage†
    Adults

    400 mg PO 3 times per day or 200 mg PO 5 times per day for a total of at least 10 days of therapy or until clinical resolution occurs after initial IV therapy.[59799] In HIV-infected patients, guidelines recommend 400 mg PO 3 times per day for 5 to 10 days or until clinical resolution occurs.[34362]

    Adolescents

    1,000 mg/day PO divided into 3 to 5 doses for 7 to 14 days is recommended by the American Academy of Pediatrics (AAP).[63245] In HIV-infected patients, guidelines recommend 400 mg PO 3 times per day for 5 to 10 days or until clinical resolution occurs.[34362]

    Children 2 to 12 years

    1,000 mg/day PO divided into 3 to 5 doses (Max: 80 mg/kg/day) for 7 to 14 days is recommended by the American Academy of Pediatrics (AAP). In HIV-infected patients, guidelines recommend 20 mg/kg/dose PO 4 times daily (Max: 400 mg/dose) for 7 to 10 days for mild symptomatic gingivostomatitis.

    For the treatment of acute herpes simplex keratitis (dendritic keratitis).
    Ophthalmic dosage
    Adults

    Apply a 1 cm (0.5 inch) ribbon of ointment into the lower cul-de-sac of the affected eye 5-times daily (approximately every 3 hours while awake) until the corneal ulcer heals. Then reduce the dose to a 1 cm ribbon 3-times daily for an additional 7 days.[64038]

    Children and Adolescents 2 years and older

    Apply a 1 cm (0.5 inch) ribbon of ointment into the lower cul-de-sac of the affected eye 5-times daily (approximately every 3 hours while awake) until the corneal ulcer heals. Then reduce the dose to a 1 cm ribbon 3-times daily for an additional 7 days.[64038]

    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] [63245] 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.[63245]

    For chronic suppression of recurrent herpes labialis† (i.e., herpes labialis prophylaxis†).
    Oral dosage
    Adults

    400 mg PO twice daily has been effective in decreasing the frequency of recurrent episodes.

    Children and Adolescents

    10 mg/kg/dose PO 3 times per day (Max: 1,000 mg/day) may be beneficial for some patients with frequent recurrences. Reevaluate after 6 to 12 months of continuous therapy. No clinical studies of prophylactic therapy for herpes labialis have been performed in children.[63245] For HIV-infected patients, 20 mg/kg/dose PO twice daily (Max: 800 mg/dose) is recommended by guidelines. 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.
    Intravenous dosage
    Adults

    250 mg/m2/dose IV every 8 hours beginning 1 day prior to transplant and continuing until marrow engraftment has been recommended in bone marrow transplant recipients.[24258] The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients.[34408]

    Infants, Children, and Adolescents

    15 mg/kg/day IV divided every 8 hours during the period of risk. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients.

    Oral dosage
    Children and Adolescents 2 to 17 years

    600 to 1,000 mg/day PO in 3 to 5 divided doses during the period of risk.

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

    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 secondary herpes simplex ocular infection prophylaxis†.
    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.

    For the treatment of herpes zoster ocular infection† (herpes zoster ophthalmicus†).
    For the oral use of acyclovir for the treatment of herpes zoster ocular infection.
    Oral dosage
    Adults

    800 mg PO 5 times daily for 7 days. Clinical practice guidelines recommend famciclovir or valacyclovir.

    For the intravenous use of acyclovir for the treatment of herpes zoster ocular infection.
    Intravenous dosage
    Adults

    10 mg/kg or 500 mg/m2 IV every 8 hours for retinitis or severely immunocompromised patients. Convert to oral antiviral therapy when infection is controlled and for remainder of 7-day treatment course.

    For the treatment of ocular infections [acute retinal necrosis (ARN)† and progressive outer retinal necrosis (PORN)†] due to varicella-zoster virus in HIV-infected patients.
    For the treatment of acute retinal necrosis (ARN)†.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV every 8 hours for 10 to 14 days plus intravitreal ganciclovir injection twice weekly for 1 to 2 doses is recommended by the HIV guidelines, then oral valacyclovir for at least 14 weeks. 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 twice weekly for 1 to 2 doses is recommended by the HIV guidelines, then oral valacyclovir for at least 14 weeks. 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 for 4 to 6 weeks is recommended by the HIV guidelines. FDA-approved labeling recommends the use of ideal body weight when dosing obese adults. Similar consideration should be given to pediatric patients.

    Oral dosage
    Infants and Children

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

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

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

    Adolescents

    10 mg/kg/dose IV every 8 hours plus intravitreal ganciclovir and/or foscarnet injection twice weekly is recommended by the HIV guidelines. The duration of therapy is not well defined and should be based on clinical, virologic, and immunologic responses in consultation with ophthalmologist. 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

    All oral dosage forms: May be administered without regard to meals.[28977]

    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.

    Ophthalmic Administration

    Ointment:
    Instruct patient on proper instillation of ophthalmic ointment.
    Wash hands before applying the ophthalmic ointment.
    Using the index finger, pull down the lower lid of the affected eye to form a pocket.
    Apply ointment in the pocket formed by the lower lid.
    Close the eye for 1 to 2 minutes.
    Any excess ointment can be wiped away.[64038]

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    - Use within 24 hours from time of preparation
    Sitavig:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zovirax:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 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.[54268] [64038] 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. The buccal tablet contains milk protein concentrate and is, therefore, contraindicated in patients with milk protein hypersensitivity.[54268]

    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.[41766]

    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 complete or well-controlled pregnancy studies have been performed to evaluate the use of acyclovir in humans. Acyclovir was not found to be teratogenic in standard animal studies. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 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. Systemic use should be avoided during pregnancy unless the potential benefits outweigh the possible risks to the fetus.[28977] [41766] [43519] [54268]

    Breast-feeding

    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 considers maternal use of systemic acyclovir to be compatible with breast-feeding.[27500] Exposure of the infant after maternal use of topical administration of acyclovir is minimal, provided the treatment area does not involve the breast. Women who have active herpetic lesions on or near the breast should avoid nursing until the lesions have completely resolved. There are no data regarding the presence of acyclovir in human milk following ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safe and effective use of acyclovir ointment in neonates, infants, children, and adolescents has not been established. Safety and efficacy of acyclovir cream have not been established in neonates, infants, and children less than 12 years of age. Use of the buccal tablet should be avoided in pediatric populations because of its complex administration procedure and the potential risk of choking. Oral and ophthalmic formulations are not recommended by the manufacturer for use in children younger than 2 years of age, infants, and neonates. The intravenous formulations are approved for all pediatric populations, including neonates.[28977] [41766] [43519] [43520] [54268] [64038]

    Ophthalmic administration

    Acyclovir topical cream and ointment products are approved for external use only; avoid ophthalmic administration or use inside the mouth or nose. To treat acute herpetic keratitis, use the 3% ophthalmic ointment.

    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
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    anaphylactoid reactions / 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
    edema / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    peripheral edema / Delayed / 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
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    fever / Early / Incidence not known
    myalgia / Early / Incidence not known

    DRUG INTERACTIONS

    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: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Aminoglycosides: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    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 changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as 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.
    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: (Severe) 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.
    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.
    Colchicine; 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.
    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 changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as 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.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as 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 Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as 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; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as 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 disoproxil fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    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.
    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 conjuction 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.
    Gallium Ga 68 Dotatate: (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.
    Gentamicin: (Major) 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.
    Kanamycin: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    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. 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.
    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.
    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: (Major) 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: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Polymyxins: (Major) 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.
    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.
    Streptomycin: (Major) 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 serum creatinine and phosphorus if tenofovir alafenamide 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.
    Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide 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.
    Tenofovir, PMPA: (Moderate) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir with acyclovir may increase the serum concentrations of tenofovir via competition for renal tubular secretion.
    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: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Varicella-Zoster Virus Vaccine, Live: (Major) If possible, discontinue acyclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. 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.

    PREGNANCY AND LACTATION

    Pregnancy

    No complete or well-controlled pregnancy studies have been performed to evaluate the use of acyclovir in humans. Acyclovir was not found to be teratogenic in standard animal studies. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 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. Systemic use should be avoided during pregnancy unless the potential benefits outweigh the possible risks to the fetus.[28977] [41766] [43519] [54268]

    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 considers maternal use of systemic acyclovir to be compatible with breast-feeding.[27500] Exposure of the infant after maternal use of topical administration of acyclovir is minimal, provided the treatment area does not involve the breast. Women who have active herpetic lesions on or near the breast should avoid nursing until the lesions have completely resolved. There are no data regarding the presence of acyclovir in human milk following ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). Acyclovir inhibits viral DNA synthesis and must be phosphorylated intracellularly to be active. Acyclovir is converted to the monophosphate by viral thymidine kinase (TK), then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Acyclovir triphosphate stops replication of herpes viral DNA by the following 3 mechanisms: competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.[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]
     
    Viral resistance to acyclovir may occur due to loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA-polymerase sensitivity. Alterations in these enzymes occur due to point mutations or base insertions or deletions in the specific genes. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents activated by thymidine kinase (e.g., ganciclovir or penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in 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 of 440 mcg/mL 8 hours after application of the tablet, with concentrations declining to 88.1 mcg/mL after 24 hours. Acyclovir concentrations in the plasma are delayed 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]
     
    Ophthalmic Route
    Concentrations of acyclovir have not been detected in the blood following ophthalmic administration; however, therapeutically irrelevant trace quantities have been identified in the urine.[64038]