Acyclovir (Systemic)

(ay SYE kloe veer)

Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Absorption

Oral: 15% to 30%

Distribution

Vd: Neonates to 3 months of age: 28.8 L/1.73 m2; Children 1 to 2 years: 31.6 L/1.73 m2; Children 2 to 7 years: 42 L/1.73 m2; Adults: 0.8 L/kg (63.6 L). Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF); CSF acyclovir concentration is 50% of serum concentration

Metabolism

Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes

Excretion

Urine (62% to 90% as unchanged drug and metabolite)

Time to Peak

Serum: Oral: Within 1.5 to 2 hours

Half-Life Elimination

Terminal: Neonates: 4 hours; Children 1 to 12 years: 2 to 3 hours; Adults: 2 to 3.5 hours (with normal renal function); 20 hours (ESRD) (Gorlitzsky 2017); hemodialysis: ~5 hours

Protein Binding

<9% to 33%

Bell palsy (new onset)

There is insufficient evidence to recommend acyclovir for the treatment of Bell palsy. However, AAN guidelines state that antivirals may, at best, provide a modest increase in recovery and may be reserved as an option.

Herpes simplex virus (HSV), genital infection in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, oral acyclovir is an effective and recommended agent in the management of initial or recurrent episodes or as chronic suppressive therapy of genital herpes in adolescent and adult HIV-infected patients.

Herpes simplex virus (HSV), mucocutaneous infection in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, oral acyclovir is an effective and recommended agent in the management of mucocutaneous HSV infections in adolescent and adult HIV-infected patients.

Herpes simplex virus (HSV), orolabial (cold sores) infection in immunocompetent patients

Data from two randomized double-blind placebo-controlled studies and one other study of lower quality support the use of systemic acyclovir in the treatment of orolabial HSV infection [Amir 1997], [Rooney 1993], [ Spruance 1990].

Herpes simplex virus (HSV), orolabial (cold sores) infection in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, oral acyclovir is an effective and recommended agent in the management of orolabial HSV infections in adolescent and adult HIV-positive patients.

Herpes zoster (shingles) in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, oral acyclovir is an effective and recommended alternative agent in the management of acute localized herpes zoster (shingles) in adolescent and adult HIV-infected patients.

Infection (cytomegalovirus [CMV]) prophylaxis in low-risk allogeneic hematopoietic stem cell transplant (HSCT)

Based on collaborative guidelines for preventing infectious complications in HSCT recipients, acyclovir is recommended as an alternative (to ganciclovir) as prophylactic therapy after transplant [Tomblyn 2009].

Infection (HSV and VZV reactivation) prophylaxis in neutropenia

Guidelines recommend the use of antiviral prophylaxis in HSV- and VZV-seropositive HSCT recipients and acute myeloid leukemia patients to reduce the risk of HSV and VZV reactivation.

Varicella (chickenpox) in HIV-infected patients (adolescent and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, acyclovir is an effective and recommended agent in the treatment of varicella (chickenpox) in adolescent and adult HIV-infected patients.

Varicella-zoster virus acute retinal necrosis (ARN) in HIV-infected patients (adolescent and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, intravenous acyclovir is an effective and recommended agent in the management of varicella-zoster virus acute retinal necrosis (ARN) in adolescent and adult HIV-infected patients.

Additional Off-Label Uses

Disseminated primary eczema herpeticum; Herpes simplex–associated erythema multiforme; Herpes zoster encephalitis

Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation

Herpes simplex virus (HSV), genital infection:

IV: Children ≥12 years and Adolescents: Immunocompetent: Initial episode, severe: Manufacturer’s labeling: 5 mg/kg/dose every 8 hours for 5 to 7 days

Oral:

Infants and Children <12 years: Immunocompetent (off-label use):

Initial episode: 40 to 80 mg/kg/day divided into 3 to 4 doses for 5-10 days (maximum: 1,000 mg daily) (Red Book [AAP 2012])

Chronic suppression: 40 to 80 mg/kg/day in 3 divided doses for ≤12 months; (maximum: 1,000 mg daily) (Red Book [AAP 2009])

Children ≥12 years and Adolescents: Immunocompetent (off-label use):

Initial episode: 200 mg every 4 hours while awake (5 times daily) or 400 mg 3 times daily for 7 to 10 days; treatment can be extended beyond 10 days if healing is not complete (Red Book [AAP 2012])

Chronic suppression: 800 mg daily in 2 divided doses for ≤12 continuous months (Red Book [AAP 2012])

Children: HIV-exposed/-positive (off-label use):

Children <45 kg:

Initial episode: 60 mg/kg/day divided into 3 doses daily for 5 to 14 days (maximum: 1,200 mg daily) (CDC 2009)

Chronic suppression: 20 mg/kg/dose twice daily (maximum dose: 400 mg) (CDC 2009)

Children ≥45 kg:

Initial episode: 400 mg twice daily for 5 to 14 days (CDC 2009)

Chronic suppression: 20 mg/kg/dose twice daily (maximum dose: 400 mg) (CDC 2009)

Children <12 years: Recurrence: Immunocompetent: Oral: 20 to 25 mg/kg/dose twice daily; maximum dose: 400 mg (Bradley 2011)

Children ≥12 years: Recurrence: Immunocompetent:

Manufacturer’s labeling: 200 mg every 4 hours while awake (5 times daily) for 5 days

Alternate recommendation: 400 mg 3 times daily for 5 days or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days (CDC [Workowski 2015]; Red Book [AAP 2015])

Adolescents: HIV-positive patients: (off-label use): Refer to adult dosing.

HSV encephalitis: IV:

Infants and Children 3 months to <12 years:

Immunocompetent:

Manufacturer's labeling: 20 mg/kg/dose every 8 hours for 10 days. Note: Doses ≥20 mg/kg may be associated with a higher incidence of nephrotoxicity (Red Book [AAP 2012])

Alternate recommendation: 10 to 15 mg/kg/dose every 8 hours for 14 to 21 days (Red Book [AAP 2012])

HIV-exposed/-positive: 10 mg/kg/dose every 8 hours for 21 days; do not discontinue therapy until a repeat HSV DNA PCR assay of the cerebrospinal fluid is negative (CDC 2009)

Children ≥12 years and Adolescents: Independent of HIV status:

Manufacturer's labeling: 10 mg/kg/dose every 8 hours for 10 days

Alternate recommendation: 10 mg/kg/dose every 8 hours for 14 to 21 days (Red Book [AAP 2012])

HSV gingivostomatitis (off-label use): HIV-exposed/-positive:

Mild, symptomatic: Oral: Infants and Children: 20 mg/kg/dose 3 times daily for 5 to 10 days (maximum dose: 400 mg) (CDC 2009)

Moderate to severe, symptomatic: IV: Infants and Children: 5 to 10 mg/kg/dose every 8 hours; Note: switch to oral therapy once lesions begin to regress (CDC 2009)

HSV, mucocutaneous treatment:

Immunocompromised:

IV:

Infants, Children, and Adolescents: 10 mg/kg/dose every 8 hours for 7 to 14 days (Red Book [AAP 2012])

Oral (off-label use):

Children ≥2 years and Adolescents: 1,000 mg daily in 3 to 5 divided doses for 7 to 14 days; some suggest the maximum daily dose should not exceed 80 mg/kg/day (Red Book [AAP 2009]; Red Book [AAP 2012])

HIV-infected patients (off-label use): Adolescents: IV, Oral: Refer to adult dosing.

Suppression, chronic (cutaneous, ocular) episodes: Immunocompromised: Oral:

Infants and Children (HIV-exposed/-positive): 20 mg/kg/dose twice daily for 5 to 14 days; maximum dose: 400 mg (CDC 2009)

Children and Adolescents ≥12 years (independent of HIV status): 400 mg twice daily for up to 12 months (Red Book [AAP 2012])

HSV, neonatal: IV: Infants: Birth to 3 months: Treatment:

Manufacturer's labeling: 10 mg/kg/dose every 8 hours for 10 days

Alternate recommendations: 20 mg/kg/dose every 8 hours for 14 days (skin and mucous membrane disease) to 21 days (disseminated disease and CNS disease) (CDC [Workowski 2015]; Kimberlin 2013; Red Book [AAP 2012])

HSV, orolabial (cold sores) (off-label use): Oral:

Immunocompetent: Chronic suppression: Children: 30 mg/kg/day in 3 divided doses for up to 12 months (maximum: 1,000 mg/day). Note: Re-evaluate after 12 months (Red Book [AAP 2012])

HIV-infected patients: Treatment: Adolescents: Refer to adult dosing.

Herpes zoster (shingles), treatment:

IV:

Immunocompetent (off-label use):

Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2012])

Children ≥1 year and Adolescents: 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose every 8 hours (Red Book [AAP 2012])

Immunocompromised:

Children <12 years: (off-label dose): 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2012])

Children ≥12 years and Adolescents: Manufacturer’s labeling: Refer to adult dosing.

HIV-infected patients: Adolescents (off-label dose): Extensive cutaneous lesions or visceral involvement: Refer to adult dosing.

Oral:

Immunocompetent:

Children ≥12 years and Adolescents (off-label dose): 800 mg 5 times daily for 5 to 7 days (Red Book [AAP 2012])

Immunocompromised: HIV-infected patients (off-label use): Acute localized infection (as an alternative to valacyclovir or famciclovir): Adolescents: Refer to adult dosing.

Prevention of HSV reactivation in HIV-exposed/-positive patients (off-label use): Oral: Children: 20 mg/kg/dose twice daily (maximum: 400 mg per dose) (CDC 2009)

Prevention of early HSV reactivation in seropositive hematopoietic stem cell transplant (HSCT) recipients (off-label use): Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days) (Tomblyn 2009):

Oral:

Children and Adolescents <40 kg (alternate therapy): 60 to 90 mg/kg/day in 2 to 3 divided doses

Children and Adolescents ≥40 kg: Refer to adult dosing.

IV:

Children and Adolescents <40 kg: 250 mg/m2 every 8 hours or 125 mg/m2 every 6 hours (maximum daily dose: 80 mg/kg/day)

Children and Adolescents ≥40 kg: Refer to adult dosing.

Prevention of late HSV reactivation in seropositive HSCT recipients (off-label use): Note: Continue therapy for 1 year after HSCT (Tomblyn 2009).

Children and Adolescents <40 kg: Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses (maximum dose: 800 mg twice daily)

Children and Adolescents ≥40 kg: Refer to adult dosing.

Prevention of VZV reactivation in HSCT recipients (off-label use): Note: Continue therapy for 1 year after HSCT (Tomblyn 2009)

Children and Adolescents <40 kg: Oral: 60 to 80 mg/kg/day in 2 to 3 divided doses

Children and Adolescents ≥40 kg: Refer to adult dosing.

Prophylaxis of CMV in low-risk allogeneic HSCT (off-label use; alternate therapy): Note: Begin at engraftment and continue to day 100; requires close monitoring for CMV reactivation (due to weak activity); not for use in patients at high risk for CMV disease (Tomblyn 2009)

Oral:

Infants, Children, and Adolescents <40 kg: 600 mg/m2 4 times daily

Children and Adolescents ≥40 kg: 800 mg 4 times daily

IV: Infants, Children, and Adolescents: 500 mg/m2 every 8 hours

Varicella (chickenpox), treatment: Begin treatment within the first 24 hours of rash onset:

Oral:

Immunocompetent:

Children ≥2 years and ≤40 kg: 20 mg/kg/dose (maximum: 800 mg per dose) 4 times daily for 5 days

Children >40 kg: Refer to adult dosing.

HIV-infected patients (off-label use):

Infants and Children: Mild, uncomplicated disease and no or moderate immune suppression: 20 mg/kg/dose (maximum dose: 800 mg) 4 times daily for 7 to 10 days or until no new lesions for 48 hours (CDC 2009)

Adolescents: Uncomplicated cases (as an alternative to valacyclovir or famciclovir): Refer to adult dosing.

IV:

Immunocompetent (off-label use): Children ≥2 years: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 10 days (CDC 2009; Red Book [AAP 2012])

Immunocompromised (off-label use):

Infants (off-label dose): 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2012])

Children and Adolescents (off-label dose): 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose every 8 hours (Red Book [AAP 2012])

HIV-exposed/-positive (off-label use):

Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days or until no new lesions for 48 hours (CDC 2009)

Children ≥1 year: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 10 days or until no new lesions for 48 hours (CDC 2009)

Adolescents: Refer to adult dosing.

Varicella-zoster virus acute retinal necrosis in HIV-exposed/-positive patients (off-label use): IV:

Infants and Children: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days, followed by oral acyclovir or valacyclovir for 4 to 6 weeks (CDC 2009)

Adolescents: Refer to adult dosing.

Note: Monitor closely for neurotoxicity (Chowdhury 2016)

Oral:

CrCl 10 to 25 mL/minute/1.73 m2: Normal dosing regimen 800 mg 5 times daily: Administer 800 mg every 8 hours

CrCl <10 mL/minute/1.73 m2:

Normal dosing regimen 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours

Normal dosing regimen 800 mg 5 times daily: Administer 200 mg every 12 hours (IDSA [Gupta 2005])

Intermittent hemodialysis (IHD): Dialyzable (60% reduction following a 6-hour session):

Normal dosing regimen 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours; administer after hemodialysis on dialysis days

Normal dosing regimen 800 mg 5 times daily: Administer a loading dose of 400 mg and a maintenance dose of 200 mg twice daily plus a single 400 mg dose after each dialysis (Almond 1995). Note: Dose based on pharmacokinetic data and computer modeling.

Continuous ambulatory peritoneal dialysis (CAPD): 600 to 800 mg daily (Stathoulopoulou 1996)

IV:

CrCl 25 to 50 mL/minute/1.73 m2: Administer recommended dose every 12 hours

CrCl 10 to 25 mL/minute/1.73 m2: Administer recommended dose every 24 hours

CrCl <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (60% reduction following a 6-hour session): 2.5-5 mg/kg every 24 hours (Heintz 2009). Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions.

Peritoneal dialysis (PD): Administer 50% of normal dose once daily; no supplemental dose needed (Aronoff 2007)

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: 5 to 10 mg/kg every 24 hours

CVVHD/CVVHDF: 5 to 10 mg/kg every 12 to 24 hours

Note: The higher end of dosage range (eg, 10 mg/kg every 12 hours for CVVHDF) is recommended for viral meningoencephalitis and varicella-zoster virus infections.

Oral, IV: There are no dosage adjustments provided in the manufacturer's labeling; use caution in patients with severe impairment.

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Acyclovir-Valacyclovir. Avoid combination

Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Talimogene Laherparepvec: Antiherpetic Antivirals may diminish the therapeutic effect of Talimogene Laherparepvec. Monitor therapy

Tenofovir Products: Acyclovir-Valacyclovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Varicella Virus Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Varicella Virus Vaccine. Management: When possible, avoid use of acyclovir or valacyclovir within the 24 hours prior to administration of the varicella vaccine, and avoid use of these antiviral agents for 14 days after vaccination. Avoid combination

Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Monitor therapy

Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Avoid combination