ACYCLOVIR SODIUM
  • ACYCLOVIR SODIUM

  • QTY 15 • 500 MG • VIAL • Near 77381

ACYCLOVIR (ay SYE kloe veer) is an antiviral medicine. It is used to treat or prevent infections caused by certain kinds of viruses. Examples of these infections include herpes and shingles. This medicine will not cure herpes.

ACYCLOVIR SODIUM Pediatric Monographs
  • General Administration Information
    For storage information, see the specific product information within the How Supplied section.

    Route-Specific Administration

    Oral Administration
    -May be administered without regard to meals.
    Oral Liquid Formulations
    -Shake the suspension well prior to administration. Measure the suspension with a calibrated oral dosing device to give accurate dosage.



    Injectable Administration
    -Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    -Parenteral acyclovir is for intravenous use only.
    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.

    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).
    -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.-Institute for Safe Medication Practices (ISMP)/Vermont Oxford Network (VON) Recommended Standard Concentration for Neonatal Administration: 7 mg/mL

    -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.

    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.



    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.

    The most common adverse reactions (2% to 10%) associated with the use of acyclovir ophthalmic ointment include ocular pain (stinging), punctuate keratitis, and follicular conjunctivitis. Rare cases of blepharitis have also been reported.

    Systemic acyclovir is associated with nephrotoxicity that occurs as a result of crystallization of the drug within the nephron. Acyclovir has low solubility in urine; low urine volume associated with dehydration may contribute to crystalluria. Crystalluria can lead to azotemia, renal tubular obstruction, renal failure, and even death in severe cases. Crystalluria is more likely to occur during administration of large, parenteral doses or in patients who are dehydrated. Rapid or bolus infusions of acyclovir have been associated with renal toxicity; therefore, intravenous infusions must be administered over at least 1 hour. During clinical trials, transient elevations of serum creatinine and blood urea nitrogen (BUN) were observed in 5% to 10% of acyclovir recipients (ages not specified), with the higher incidence occurring after rapid (less than 10 minute) infusions. In a neonatal clinical trial, Grade 3 or 4 increase in creatinine was reported in 6% (n = 4/64) of patients. Ensure that patients are adequately hydrated and maintain a high urine flow to minimize the potential for crystalluria, and monitor renal and fluid status during therapy. In the event of renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored. During postmarketing use of acyclovir, renal pain, which may be associated with renal failure, has been reported.

    Neutropenia has been reported in less than 1% of adult patients during clinical trials; however, it is one of the most common adverse reactions of acyclovir therapy in neonates occurring in approximately 20% to 25% of patients. Monitor neutrophil counts routinely in neonates receiving acyclovir; consider a dosage adjustment or administration of granulocyte colony-stimulating factor if the absolute neutrophil count (ANC) remains below 500/mm3 for a prolonged period. In 1 clinical trial, 6 of 29 (21%) neonates who received acyclovir 60 mg/kg/day IV for neonatal herpes simplex virus infection experienced neutropenia, including 1 patient with an ANC less than 500/mm3. In all 6 cases, the ANC recovered during continuation of acyclovir or after completion of therapy. In another clinical trial in neonates in which most received 60 mg/kg/day IV for neonatal herpes simplex virus infection, an ANC of 500 to 1,000 cells/mm3 and less than 500 cells/mm3 was reported in 16% (n = 10/64) and 3% (n = 2/64) of patients, respectively. In 2 placebo-controlled trials of oral acyclovir for long-term suppressive therapy, 25% of patients with CNS disease and 20% of patients with disease limited to skin, eyes, and mouth developed an ANC less than 500/mm3. The incidence of neutropenia in other pediatric populations is not clear; however, the incidence is likely to be less than that in neonates.

    Neurotoxicity has been reported during systemic acyclovir administration, especially when administered in high doses and/or in patients with renal, hepatic, or electrolyte abnormalities. Neurologic adverse reactions usually occur within 1 to 2 days of achieving the maximum acyclovir concentration and may not be directly correlated with the present acyclovir serum concentrations. Neurotoxic adverse reactions occur in approximately 1% of intravenous acyclovir recipients (age not specified) and are characterized by either coma, confusion, encephalopathy, hallucinations, lethargy, obtundation, agitation, seizures, or tremor. During oral acyclovir clinical trials, malaise and headache were reported in 11.5% and 2.2%, respectively, of drug recipients; these have also been reported with intravenous acyclovir use. Additional neurologic adverse reactions noted during postmarketing use of systemic acyclovir, include aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, drowsiness, dysarthria, encephalopathy, fatigue, hallucinations, headache, obtundation, paresthesias, psychosis, seizures, and tremors.

    Injection site reaction, manifested as inflammation or phlebitis, occurs in approximately 9% of parenteral acyclovir recipients. Avoid using the same IV site if a reaction develops. More concentrated acyclovir solutions are associated with an increased risk of infusion-related reactions; final acyclovir infusion concentrations more than 7 mg/mL are not recommended. Severe local inflammatory reactions, including tissue necrosis, have occurred after infusion of acyclovir into extravascular tissues.

    During clinical trials of systemic acyclovir formulations, nausea (2.4% to 7%) and vomiting (2.7% to 7%) were the most commonly reported gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.4% to 3.2% of patients treated with oral acyclovir and has been observed with intravenous use in clinical practice. Elevated hepatic enzymes (1% to 2%) were noted with the intravenous formulation. Other GI adverse reactions that have been reported by patients receiving systemic acyclovir include abdominal pain or gastrointestinal distress, anorexia, hepatitis, hyperbilirubinemia, and jaundice. In a neonatal clinical trial, total bilirubin Grade 3 or 4 toxicity was reported in 4% (n = 2/52) of patients.

    Dermatologic adverse reactions have occurred in patients receiving systemic and topical acyclovir formulations. Pruritus was reported in 2% of patients during clinical trials of the intravenous formulation and with the oral formulations in postmarketing reports; local pruritus was reported with the cream (1%) and ointment (4%). Rash was reported in 2% of patients during clinical trials of the intravenous formulation and with the oral and topical ointment formulations in postmarketing reports. During intravenous acyclovir clinical trials, 2% of patients developed urticaria (hives). With systemic acyclovir formulations (both oral and intravenous) there have been postmarketing reports of alopecia, photosensitivity rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In topical acyclovir clinical trials, skin irritation (manifested as stinging, burning, pain) was experienced by 1% to 2% of patients after application of the topical cream and 30% of patients receiving acyclovir ointment. Other dermatologic adverse reactions experienced by topical product recipients during clinical trials included contact sensitization (2%, cream), peeling skin or desquamation (1%, cream), dry and cracked lips (1%, cream), and xerosis (1%, cream). Postmarketing dermatologic adverse reactions associated with topical formulations include application site inflammation, contact dermatitis, eczema, edema, and pruritus. Urticaria has been reported with the ophthalmic formulation in postmarketing surveillance.

    Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have occurred in immunocompromised patients receiving systemic acyclovir therapy; some of these events have resulted in patient death.

    Postmarketing adverse reactions associated with systemic acyclovir (both oral and IV) include anaphylactoid reactions, angioedema, peripheral edema, hypotension (IV only), fever, myalgia, generalized pain, and visual impairment. Cases of anaphylactoid reactions and angioedema have also been noted after use of the topical cream and ophthalmic ointment.

    With the exception of neutropenia in neonates, hematologic adverse reactions occur infrequently with acyclovir therapy. During IV acyclovir clinical trials, the following adverse reactions were observed in less than 1% of drug recipients: anemia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia. In a neonatal clinical trial, hemoglobin less than 8 g/dL was reported in 13% (n = 8/64) of patients. A platelet count of 50,000 to 100,000 cells/mm3 and less than 50,000 cells/mm3 was reported in 10% (n = 6/63) and 5% (n = 3/63) of patients, respectively. Cases of hematuria were also noted in patients treated with IV acyclovir during clinical trials. During the postmarketing period, hematologic adverse reactions associated with the use of systemic acyclovir (both oral and IV) included anemia, disseminated intravascular coagulation (DIC) (IV formulation only), hemolysis (IV formulation only), leukocytoclastic vasculitis, leukopenia, lymphadenopathy, and thrombocytopenia.

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

    Use systemic acyclovir with caution in patients with renal dysfunction; acyclovir is renally eliminated. Patients with renal impairment are at increased risk of acyclovir-induced neurotoxicity due to high acyclovir concentrations. Patients with renal impairment or renal failure should receive lower doses of acyclovir at longer intervals. To prevent crystalluria and renal toxicity, patients should be well-hydrated to maintain a high urine volume and avoid dehydration during therapy with acyclovir. Renal failure has occurred with acyclovir therapy. Patients receiving other potentially nephrotoxic drugs 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.

    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.

    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. Acyclovir cream is indicated for immunocompetent patients only; efficacy has not been established for immunocompromised patients.

    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.

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

    Acyclovir for injection is for intravenous use only; take care to avoid intramuscular administration or subcutaneous administration. Extravasation may cause phlebitis and inflammation of surrounding tissues.

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

    Description: Acyclovir is an antiviral agent with activity primarily against herpes viruses (e.g., herpes simplex virus and varicella-zoster virus ). Acyclovir is approximately 10-times more potent against HSV-1 and HSV-2 than against VZV. Acyclovir is the antiviral of choice for neonatal HSV and VZV infections. Because systemic herpes virus infections can result in devastating complications in neonates and infants, intravenous acyclovir should be initiated at first suspicion of herpes virus infection. Neutropenia is one of the most common adverse reactions of acyclovir therapy in neonates occurring in approximately 20% to 25% of patients. Although acyclovir is approved for VZV in immunocompetent patients, the viral infection is usually self-limiting and therapy is not needed. Acyclovir is used in immunocompromised patients (e.g., HIV, oncology, transplant) to shorten the clinical course of herpes virus infections and may be used for prophylaxis to suppress the reactivation of infection. After exposure to long-term acyclovir therapy, HSV and VZV resistance has been reported. Acyclovir is FDA-approved for use in pediatric patients as young as neonates.

    Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus
    NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

    This drug may also have activity against the following microorganisms: B virus (cercopithecine herpesvirus), cytomegalovirus (CMV)
    NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

    For the treatment of neonatal herpes simplex virus infection:
    Intravenous dosage:
    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.
    Neonates 34 weeks postmenstrual age and older: 20 mg/kg/dose IV every 8 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.
    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.

    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. The dose should be adjusted each month for growth. Absolute neutrophil counts should be assessed 2 to 4 weeks after suppressive therapy start and then monthly thereafter during treatment.

    For the treatment of herpes simplex encephalitis:
    NOTE: For congenital herpes, see neonatal herpes simplex virus infection.
    Intravenous dosage:
    Infants 1 to 2 months*: 20 mg/kg/dose IV every 8 hours for 21 days.
    Infants and Children 3 months to 11 years: 10 to 15 mg/kg/dose IV every 8 hours for 14 to 21 days. A dose of 500 mg/m2/dose IV every 8 hours for 10 to 14 days has also been recommended. 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. In HIV-infected patients, guidelines recommend treatment for 21 days. 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 the 20 mg/kg/dose. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    Children and Adolescents 12 to 17 years: 10 mg/kg/dose IV every 8 hours for 14 to 21 days. The FDA-approved labeling recommends a duration of 10 days; however, relapses have occurred with 10-day treatment courses. In HIV-infected patients, guidelines recommend treatment for 21 days. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.

    For the treatment of herpes labialis (i.e., cold sores) or herpes fibrilis caused by herpes simplex virus:
    Oral dosage*:
    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. 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.
    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. For HIV-infected patients, guidelines recommend 400 mg PO 3 times daily for 5 to 10 days.
    Intravenous dosage:
    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. 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.
    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. Once lesions begin to regress, a change to oral dosing is recommended.
    Topical dosage (cream):
    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.

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

    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:
    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). In HIV-infected patients with disseminated disease, 10 to 15 mg/kg/dose IV every 8 hours for 21 days is recommended.
    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). The FDA-approved labeling recommends 7 days of therapy for immunocompromised patients. In HIV-infected patients with disseminated disease, 10 to 15 mg/kg/dose IV every 8 hours for 21 days is recommended. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    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). In HIV-infected patients with disseminated disease, treat for 21 days. 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. Similar consideration should be given to pediatric patients.
    Oral dosage*:
    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.
    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). In HIV-infected patients, guidelines recommend 400 mg PO 3 times per day for 5 to 10 days or until clinical resolution occurs.

    For the treatment of herpes genitalis caused by herpes simplex virus:
    -for the treatment of initial clinical episode of herpes genitalis:
    Intravenous dosage:
    Children and Adolescents 12 to 17 years: 5 mg/kg/dose IV every 8 hours for 5 to 7 days. The FDA-approved labeling recommends using ideal body weight when dosing obese adults. Similar considerations should be given to pediatric patients.
    Oral dosage*:
    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.
    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.
    -for the treatment of recurrent herpes genitalis*:
    Oral dosage:
    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:
    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. 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.

    For primary herpes simplex infection prophylaxis* in immunocompromised hosts who are HSV seropositive:
    Intravenous dosage:
    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 secondary herpes simplex ocular infection prophylaxis*:
    Oral dosage:
    Children and Adolescents 12 to 17 years: 400 mg PO twice daily for at least 12 months.

    For the treatment of varicella (chickenpox) infection:
    -for the treatment of varicella (chickenpox) in immunocompetent patients:
    NOTE: In general, acyclovir is not recommended for routine use for the treatment of varicella infections in otherwise healthy children at low risk for complications. Oral acyclovir should be considered for those at increased risk of moderate to severe varicella, such as unvaccinated adolescents, patients with chronic cutaneous or pulmonary conditions, patients receiving long-term salicylate therapy, and patients receiving short or intermittent courses of corticosteroids. Intravenous acyclovir is recommended for those with severe infection requiring hospitalization.
    Oral dosage:
    Children and Adolescents 2 to 17 years: 20 mg/kg/dose PO 4 times per day (Max: 800 mg/dose) for 5 days. Initiate therapy at the first signs of symptoms (i.e., within 24 hours).
    Intravenous dosage*:
    Children and Adolescents 2 to 17 years: 10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    -for the treatment of varicella (chickenpox) in immunocompromised patients:
    Intravenous dosage*:
    Neonates: 10 to 20 mg/kg/dose IV every 8 hours for infants presenting with a varicella infection within the first month of life.
    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.
    Children 2 to 12 years: 10 mg/kg/dose or 500 mg/m2/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. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    Adolescents: 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. Similar consideration should be given to pediatric patients.
    Oral dosage:
    NOTE: Due to poor bioavailability, experts generally recommend against the use of oral acyclovir for varicella infection in immunocompromised patients. 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.
    Infants* and Children younger than 2 years*: 20 mg/kg/dose PO 4 times per day for 7 to 10 days. In HIV-infected patients with no or moderate immune suppression, guidelines recommend treatment for 7 to 10 days or until there are no new lesions for 48 hours.
    Children 2 to 12 years: 20 mg/kg/dose PO 4 times per day (Max: 800 mg/dose) for 5 days. In HIV-infected patients with no or moderate immune suppression, guidelines recommend treatment for 7 to 10 days or until there are no new lesions for 48 hours.
    Adolescents: 800 mg PO 4 times daily for 5 days. 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.

    For post-exposure varicella (chickenpox) infection prophylaxis* in immunocompromised patients:
    Oral dosage:
    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.
    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 adolescents who lack evidence of immunity to varicella with substantial exposure to a contact with varicella or herpes zoster.

    For the treatment of herpes zoster (shingles) infection:
    -for the treatment of herpes zoster (shingles) in bone marrow and organ transplant patients, patients receiving chemotherapy, and other immunocompromised patients:
    Intravenous dosage:
    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). The FDA-approved dosage is 20 mg/kg/dose IV every 8 hours for 7 to 10 days. 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. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    Children and Adolescents 12 to 17 years: 10 mg/kg/dose IV every 8 hours for 7 to 10 days. For HIV-infected patients with trigeminal nerve involvement or extensive multi-dermatomal zoster, guidelines recommend 10 to 15 mg/kg/dose IV every 8 hours until clinical improvement then oral therapy to complete a 10 to 14 day course. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.
    Oral dosage*:
    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.
    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.
    -for the treatment of herpes zoster (shingles) in immunocompetent patients*:
    Oral dosage:
    Children and Adolescents 12 to 17 years: 800 mg PO every 4 hours given 5 times per day for 5 to 7 days.
    Intravenous dosage:
    Infants and Children younger than 2 years: 10 mg/kg/dose IV every 8 hours for 7 to 10 days.
    Children and Adolescents 2 to 17 years: 10 mg/kg/dose or 500 mg/m2/dose IV every 8 hours for 7 to 10 days. The use of ideal body weight is recommended when dosing obese adults. Similar consideration should be given to pediatric patients.

    For the treatment of ocular infections due to varicella-zoster virus in HIV-infected patients:
    -for the treatment of acute retinal necrosis (ARN)*:
    Intravenous dosage:
    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. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric 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. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. 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:
    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 an ophthalmologist. The FDA-approved labeling recommends using ideal body weight when dosing obese adult patients. Similar consideration should be given to pediatric patients.

    For cytomegalovirus (CMV) disease prophylaxis* in CMV-seropositive patients receiving bone marrow transplantation:
    Intravenous dosage:
    Children and Adolescents: 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 treatment to ganciclovir for prophylaxis of CMV infection in HSCT recipients. The FDA-approved labeling recommends the use of ideal body weight when dosing obese adult patients ; similar consideration should be given to pediatric patients.
    Oral dosage:
    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 the treatment of acute herpes simplex keratitis (dendritic keratitis):
    Ophthalmic dosage:
    Children and Adolescents 2 to 17 years: Apply a 1 cm 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.

    Maximum Dosage Limits:
    -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.
    -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.
    -Children
    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.
    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.
    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.
    -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.

    Patients with Hepatic Impairment Dosing
    No dosage adjustment needed.

    Patients with Renal Impairment Dosing
    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.

    Infants, Children, and Adolescents
    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 24 mL/min/1.73 m2: extend IV dosing interval to every 24 hours. For patients receiving 800 mg PO five 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 five 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 five times per day, reduce dose to 800 mg PO every 12 hours. For patients receiving 200 mg PO five times per day or 400 mg PO every 12 hours, reduce dose to 200 mg PO every 12 hours.

    Intermittent hemodialysis
    For IV dosing, 2.5 to 5 mg/kg/dose IV every 24 hours (based on adult data, a 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.

    Patients Undergoing Plasmapheresis
    Administer IV doses at least 3 hours before plasmapheresis.

    *non-FDA-approved indication

    Monograph content under development

    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.

    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.

    Resistance to acyclovir by herpes virus results from mutations in viral thymidine kinase and DNA polymerase that cause a loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA polymerase sensitivity. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents (e.g., foscarnet, famciclovir, and penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in infants and immunocompromised patients. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.

    Pharmacokinetics: Acyclovir is administered topically, ophthalmically, orally, and intravenously. Acyclovir distributes extensively into all tissues, with the highest concentrations in the kidneys, liver, and intestines. Cerebrospinal fluid (CSF) concentrations are approximately 50% of plasma concentrations. In adult patients, acyclovir is poorly protein bound at 9% to 33%; protein binding is independent of plasma acyclovir concentrations. Excretion is via glomerular filtration and tubular secretion, with approximately 62% to 91% of the drug excreted unchanged. The only known urinary metabolite is 9-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. The elimination half-life of acyclovir in adult patients with normal renal function is 2.5 to 3.3 hours. In general, the pharmacokinetics of acyclovir in pediatric patients older than 1 year of age are similar to those of adults.

    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.


    -Route-Specific Pharmacokinetics
    Oral Route
    Acyclovir is poorly absorbed from the GI tract, with an oral bioavailability of 10% to 20%. In adult patients, 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.

    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. 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.

    Other Route(s)
    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.


    -Special Populations
    Pediatrics
    Neonates and Infants 1 to 2 months

    In a study in neonates that was stratified by postmenstrual age (PMA; n = 28), median clearance was 3.5 mL/minute/kg, 7.5 mL/minute/kg, and 9.8 mL/minute/kg in neonates with PMA of younger than 30 weeks, 30 to 35 weeks, and 36 to 41 weeks, respectively. In another study of neonates and infants aged 0 to 3 months (n = 12), the mean clearance and elimination half-life were 4.5 mL/minute/kg and 3.8 hours, respectively, which is approximately one-half of the clearance seen in pediatric patients 3 months and older. The decreased clearance observed is consistent with the renal changes that occur during the first year of life.

    Infants 3 to 11 months, Children, and Adolescents
    In a study of pediatric patients 3 months to 12 years (n = 16) receiving IV acyclovir 30 to 60 mg/kg/day, the mean clearance and elimination half-life were 8.4 mL/minute/kg and 2.4 hours, respectively. The elimination half-life is comparable to the elimination half-life of 2.5 to 3.3 hours seen in adults.

    Renal Impairment
    In anuric adult patients, the elimination half-life of acyclovir may be as long as 19.5 hours.

    Dialysis
    Acyclovir is hemodialyzable with an extraction coefficient of 0.45 and a dialysis clearance of 82 mL/minute when using a hallow fibre single-pass dialyzer. Acyclovir peak (Cmax) and trough (Cmin) concentrations were evaluated in a study involving 6 adult patients with severe renal failure. After a single 2.5 mg/kg dose, the Cmax and Cmin during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively. For patients requiring dialysis, the mean half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentration after a 6 hour dialysis period. Acyclovir is also removed by continuous venovenous hemodialysis (CVVHD) and, to a lesser extent, by continuous arteriovenous hemodialysis (CAVHD) and CAVHD with hemofiltration. In a study, the systemic bioavailability of acyclovir after peritoneal dosing was about 61%.

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