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Acyclovir (Systemic)

Pronunciation

(ay SYE kloe veer)

Index Terms

  • Aciclovir
  • ACV
  • Acycloguanosine
  • Acyclovir Sodium
  • Zovirax

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Zovirax: 200 mg [contains fd&c blue #2 (indigotine), parabens]

Generic: 200 mg

Solution, Intravenous, as sodium [strength expressed as base]:

Generic: 50 mg/mL (10 mL, 20 mL)

Solution Reconstituted, Intravenous, as sodium [strength expressed as base]:

Generic: 500 mg (1 ea); 1000 mg (1 ea [DSC])

Suspension, Oral:

Zovirax: 200 mg/5 mL (473 mL) [contains methylparaben, propylparaben; banana flavor]

Generic: 200 mg/5 mL (473 mL)

Tablet, Oral:

Zovirax: 400 mg

Zovirax: 800 mg [contains fd&c blue #2 (indigotine)]

Generic: 400 mg, 800 mg

Brand Names: U.S.

  • Zovirax

Pharmacologic Category

  • Antiviral Agent

Pharmacology

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: Poorly absorbed; absorption improves marginally with multiple small doses vs. one large daily dose (de Miranda 1983)

Distribution

Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF) (de Miranda 1982; Laskin 1983); CSF acyclovir concentration is ~50% of plasma concentrations.

Vdss (Blum 1982; Laskin 1983; Spector 1981):

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)

Metabolism

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

Excretion

Urine (62% to 91% as unchanged drug and metabolite)

Half-Life Elimination

Half-life elimination: Terminal: Neonates and Infants ≤3 months: 3.8 ± 1.19 hours; Infants >3 months to Children ≤12 years: 2.36 ± 0.97 hours; Adults: ~2.5 hours (with normal renal function); 20 hours (ESRD) (Gorlitzsky 2017); Hemodialysis: ~5 hours

Protein Binding

9% to 33%

Special Populations: Renal Function Impairment

Total body clearance and half-life are dependent on renal function.

Use: Labeled Indications

Oral:

Herpes zoster (shingles): Acute treatment of herpes zoster (shingles).

Herpes simplex virus (HSV), genital: Treatment of initial episodes and the management of recurrent episodes of genital herpes.

Varicella (chickenpox): Treatment of varicella (chickenpox).

Injection:

Herpes simplex virus (HSV), mucocutaneous infection in immunocompromised patients: Treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.

Herpes simplex virus (HSV), genital infection (severe): Treatment of severe initial clinical episodes of genital herpes in immunocompetent patients.

Herpes simplex encephalitis: Treatment of herpes simplex encephalitis.

Herpes simplex virus (HSV), neonatal: Treatment of neonatal herpes infections.

Herpes zoster (shingles) in immunocompromised patients: Treatment of herpes zoster (shingles) in immunocompromised patients.

Off Label Uses

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.

Cytomegalovirus (CMV) infection (prophylaxis in low-risk allogeneic HSCT recipients)

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].

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. In addition, data from a multicenter randomized, double-blind, placebo-controlled study suggest that oral acyclovir may be beneficial for the reduction of the incidence of genital ulcer disease following ART initiation in HIV/HSV-2 coinfected patients [Fife 2016]. This effect is most evident during the first quarter after ART initiation.

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 simplex virus reactivation (prevention in seropositive immunocompromised patients)

Based on the Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplant Recipients cosponsored by the Center for International Blood and Marrow Transplant Research, the National Marrow Donor Program, the European Blood and Marrow Transplant Group, and multiple other organizations, the use of acyclovir to prevent HSV reactivation (early and late) in hematopoietic cell transplant patients is effective and recommended at the beginning of conditioning and until engraftment or resolution of mucositis [Tomblyn 2009]. Acyclovir may also be used in adult patients undergoing acute myeloid leukemia (AML) induction or reinduction [Bergmann 1995], [Freifeld 2011].

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.

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 (VZV) acute retinal necrosis (ARN) in adolescent and adult HIV-infected patients.

Varicella-zoster virus reactivation (prevention in HSCT recipients)

Based on the Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplant Recipients cosponsored by the Center for International Blood and Marrow Transplant Research, the National Marrow Donor Program, the European Blood and Marrow Transplant Group, and multiple other organizations, the use of acyclovir to prevent VZV reactivation in hematopoietic cell transplant patients is effective and recommended [Tomblyn 2009].

Additional Off-Label Uses

VZV and HSV infection following solid organ transplantation; Disseminated primary eczema herpeticum; Empiric treatment of suspected encephalitis in immunocompromised patients with cancer; Herpes simplex-associated erythema multiforme; HSV gingivostomatitis

Contraindications

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

Dosing: Adult

Herpes simplex virus (HSV), genital infection:

Immunocompetent:

IV: Initial episode, severe: 5 to 10 mg/kg/dose every 8 hours for 2 to 7 days, follow with oral therapy to complete at least 10 days of therapy (CDC [Workowski 2015])

Oral:

Initial episode: 200 mg 5 times daily for 7 to 10 days or 400 mg 3 times daily for 7 to 10 days (CDC [Workowski 2015])

Recurrence: 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; Note: Initiate within 1 day of lesion onset or during the preceding prodrome (CDC [Workowski 2015]).

Chronic suppression: 400 mg twice daily for up to 12 months (followed by re-evaluation); Note: Safety and efficacy have been documented in patients receiving daily therapy with acyclovir for up to 6 years (CDC [Workowski 2015])

HIV-infected patients: See off-label uses below.

HSV encephalitis: IV: Independent of HIV status: 10 mg/kg/dose every 8 hours for 14 to 21 days (IDSA [Tunkel 2008])

HSV, mucocutaneous treatment:

Immunocompromised:

IV: 5 to 10 mg/kg/dose every 8 hours for 7 days (Leflore 2000)

Oral (off-label use): 400 mg 5 times daily for 7 days (Leflore 2000)

HIV-infected patients: See off-label uses below.

Herpes zoster (shingles) (treatment):

Immunocompromised:

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

Oral: 800 mg 5 times daily for 7 to 10 day

HIV-infected patients (HHS [OI adult 2017]):

IV: Extensive cutaneous lesions or visceral involvement: 10 to 15 mg/kg/dose every 8 hours until clinical improvement; switch to oral famciclovir or valacyclovir (preferred) or acyclovir (alternative) to complete a 10 to 14 day course when formation of new lesions has ceased and signs/symptoms of visceral infection are improving

Oral (off-label use): Acute localized infection (as an alternative to valacyclovir or famciclovir): 800 mg 5 times daily for 7 to 10 days; consider longer duration if lesions resolve slowly

Bell palsy (new onset) (off-label use): Oral: 400 mg 5 times daily for 10 days in combination with corticosteroids. Note: Benefit of the addition of antivirals to corticosteroid therapy has not been established and antivirals provide only marginal benefit over corticosteroid therapy alone (Gronseth 2012).

Cytomegalovirus (CMV) infection (prophylaxis in low-risk allogeneic HSCT recipients) (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): Adults ≥40 kg:

IV: 500 mg/m2/dose every 8 hours

Oral: 800 mg 4 times daily

Herpes simplex virus (HSV), genital infection in HIV-infected patients (off-label use):

Initial or recurrent episodes: 400 mg 3 times daily for 5 to 10 days (CDC [Workowski 2015]; HHS [OI adult 2017])

Chronic suppressive therapy: 400 mg twice daily; continue indefinitely regardless of CD4 count in patients with severe recurrences of genital herpes or in patients who want to minimize frequency of recurrences (HHS [OI adult 2017]) or 400 to 800 mg 2 to 3 times daily (CDC [Workowski 2015]). In patients beginning antiretroviral therapy and concomitant acyclovir, a reduction in the incidence of HSV-2 genital ulcers is most evident after the first 3 months of ART initiation (Fife 2016).

HSV, mucocutaneous infection in HIV-infected patients (off-label use):

IV: 5 mg/kg/dose every 8 hours; may switch to oral acyclovir after lesions begin to heal (HHS [OI adult 2017])

Oral: After initial IV therapy, may switch to 400 mg 3 times daily; continue until lesions are completely healed (HHS [OI adult 2017])

HSV, orolabial (cold sores) infection in immunocompetent patients (off-label use): Oral:

Treatment: (episodic/recurrent): 200 to 400 mg 5 times daily for 5 days (Cernik 2008; Leflore 2000; Spruance 1990)

Chronic suppression: 400 mg 2 times daily (has been clinically evaluated for up to 1 year) (Cernik 2008; Rooney 1993)

HSV, orolabial (cold sores) infection in HIV-infected patients (off-label use): Treatment: Oral: 400 mg 3 times daily for 5 to 10 days (HHS [OI adult 2017])

HSV reactivation (prevention in seropositive immunocompromised patients) (off-label use): Adults ≥40 kg:

Hematopoietic stem cell transplant (HSCT) recipients (prevention of early HSV reactivation): Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days) (Tomblyn 2009)

IV: 250 mg/m2 every 12 hours

Oral: 400 to 800 mg twice daily

HSCT recipients (prevention of late HSV reactivation): Oral: 800 mg twice daily; continue therapy for 1 year after HSCT (Tomblyn 2009).

Undergoing AML induction or reinduction therapy: Oral: 400 mg twice daily; continue during active therapy and throughout periods of neutropenia (Bergmann 1995; Freifeld 2011)

Varicella (chickenpox), treatment: Typically, valacyclovir is used for this indication since it may be administered less frequently. Begin treatment within the first 24 hours of rash onset:

IV: HIV-infected patients (off-label use): Severe or complicated cases: 10 to 15 mg/kg/dose every 8 hours for 7 to 10 days; may switch to oral famciclovir or valacyclovir (preferred) or acyclovir (alternative) after defervescence if no evidence of visceral involvement (HHS [OI adult 2017])

Oral:

Immunocompetent (>40 kg): 800 mg 4 times daily for 5 days

HIV-infected patients (off-label use): Uncomplicated cases (as an alternative to valacyclovir or famciclovir): 800 mg 5 times daily for 5 to 7 days (HHS [OI adult 2017])

Varicella-zoster virus (VZV) acute retinal necrosis (ARN) in HIV-infected patients (off-label use): IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days, followed by valacyclovir for 6 weeks plus intravitreal ganciclovir twice weekly for 1 to 2 doses (HHS [OI adult 2017])

VZV reactivation (prevention in HSCT recipients) (off-label use): Adults ≥ 40 kg: Oral: 800 mg twice daily; continue therapy for 1 year after HSCT (Tomblyn 2009)

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

Note: Obese patients should be dosed using ideal body weight. Parenteral IV doses >15 mg/kg/dose or 500 mg/m2 may be associated with an increased risk of nephrotoxicity; close monitoring of renal function is recommended (Rao 2015).

CMV prophylaxis: Low-risk allogeneic hematopoietic stem cell transplant (HSCT) in seropositive recipient. 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/dose 4 times daily; maximum dose: 800 mg/dose

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

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

Herpes zoster, acute retinal necrosis, treatment (HIV-exposed/-positive):

Initial treatment: IV: Note: Follow up IV therapy with oral acyclovir or valacyclovir maintenance therapy.

Infants: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (DHHS [pediatric] 2013)

Children: 10 to 15 mg/kg/dose or 500 mg/m2/dose every 8 hours for 10 to 14 days (DHHS [pediatric] 2013)

Adolescents: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (DHHS [adult] 2017)

Maintenance treatment; begin after 10 to 14 day course of IV acyclovir: Oral: Infants and Children: 20 mg/kg/dose 4 times daily for 4 to 6 weeks (DHHS [pediatric] 2013)

Herpes zoster (shingles), treatment:

Immunocompetent host:

Ambulatory therapy: Oral: Children ≥12 years and Adolescents: 800 mg every 4 hours (5 doses per day) for 5 to 7 days (Red Book [AAP 2015])

Hospitalized patient: IV:

Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2015])

Children 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 2015])

Immunocompromised host (non-HIV-exposed/-positive): IV: Infants, Children, and Adolescents: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2015])

HIV-exposed/-positive:

Mild, uncomplicated disease and no or moderate immune suppression: Oral:

Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 800 mg/dose; consider longer course if resolution of lesions is slow (DHHS [pediatric] 2013)

Adolescents: 800 mg 5 times daily for 7 to 10 days, longer if lesions resolve slowly (DHHS [adult] 2017)

Severe immune suppression or complicated disease; trigeminal nerve involvement, extensive multidermatomal zoster or extensive cutaneous lesions or visceral involvement: IV:

Infants: 10 mg/kg/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (DHHS [pediatric] 2013)

Children: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (DHHS [pediatric] 2013)

Adolescents: 10 to 15 mg/kg/dose every 8 hours until clinical improvement is evident, then convert to oral therapy to complete a 10- to 14-day total course of therapy (DHHS [adult] 2017)

HSV neonatal infection, treatment and suppressive therapy in very young infants (independent of HIV status):

Treatment (disseminated, CNS, or skin, eye, or mouth disease): Infants 1 to 3 months: IV: 20 mg/kg/dose every 8 hours; treatment duration: For cutaneous and mucous membrane infections (skin, eye, or mouth): 14 days; for CNS or disseminated infection: 21 days (AAP [Kimberlin 2013]; Bradley 2015; CDC [Workowski 2015]; DHHS [pediatric] 2013; Red Book [AAP 2015])

Chronic suppressive therapy following any neonatal HSV infection:

AAP Recommendation (low dose, 6-month-course): Infants: Oral: 300 mg/m2/dose every 8 hours for 6 months; begin after completion of a 14- to 21-day-course of IV therapy dependent upon type of infection (AAP [Kimberlin 2013]; Kimberlin 2011; Red Book [AAP 2015])

Alternate dosing (high dose, 2-year-course) in infants with disseminated or CNS infection (Tiffany 2005): Limited data available: Infants and Children <3 years: Oral: Begin after completion of a 21-day course of IV therapy; dosing based on a prospective trial of 16 consecutive neonates (GA: Premature: n=4; term= 12; age at treatment: Neonate: n=14; PNA >30 days: n=1) following disseminated or CNS infection; pharmacokinetic data were used to determine dosing regimen to maintain serum acyclovir concentration above target of 2 to 3 mcg/mL; treatment was continued for 2 years in 14 of 16 patients; results showed normal neurodevelopmental outcomes in 69% and normal motor development in 70%; no untoward effects were reported during the study duration.

Initial dosing: 400 mg twice daily; approximate dose: 1,200 to 1,600 mg/m2/dose twice daily

Maintenance dosing: Note: Approximate doses for patients born at term:

Infants 1 to <5 months: 400 mg twice daily

Infants 5 to <9 months: 600 mg twice daily

Infants and Children 9 to <15 months: 800 mg twice daily

Children 15 to 24 months: 1,000 mg twice daily

Note: In the trial, serum acyclovir concentrations were evaluated to assess adequacy of dosing to maintain serum concentrations above the target of 2 to 3 mcg/mL. Samples were collected 1 hour after a witnessed dose; if the acyclovir serum concentration approached or was below the target, the dose was increased to the next greater 200 mg increment. Maximum dose: 1,200 mg. Serum concentrations were evaluated every 3 months; in order to limit the phlebotomy losses, follow-up serum concentrations were not evaluated outside of routine monitoring.

HSV encephalitis, treatment:

Infants and Children 3 months to <12 years:

Non-HIV-exposed/-positive: IV: 10 to 15 mg/kg/dose every 8 hours for 14 to 21 days. Note: Due to increased risk of neurotoxicity and nephrotoxicity, higher doses (20 mg/kg) are not recommended (Red Book [AAP 2015])

HIV-exposed/-positive: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up to 20 mg/kg) may be necessary (DHHS [pediatric] 2013)

Children ≥12 years and Adolescents (independent of HIV status): IV: 10 mg/kg/dose every 8 hours for 14 to 21 days (Red Book [AAP 2015)]

HSV genital infection:

First infection, mild to moderate:

Non-HIV-exposed/-positive:

Children <12 years: Oral: 40 to 80 mg/kg/day divided in 3 to 4 doses per day for 5 to 10 days; maximum daily dose: 1,200 mg/day (Bradley 2015; Red Book [AAP 2015])

Children and Adolescents ≥12 years: Oral: 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 (CDC [Workowski 2015]; Red Book [AAP 2015])

HIV-exposed/-positive:

Children: Oral: 20 mg/kg/dose 3 times daily for 7 to 10 days; maximum dose: 400 mg/dose (DHHS [pediatric] 2013)

Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (DHHS [adult] 2017)

First infection, severe (independent of HIV status): IV: Children and Adolescents ≥12 years: 5 mg/kg/dose every 8 hours for 5 to 7 days or 5 to 10 mg/kg/dose every 8 hours for 2 to 7 days, followed with oral therapy to complete at least 10 days of therapy (CDC [Workowski 2015]; Red Book [AAP 2015])

Recurrent infection:

Children <12 years (independent of HIV status): Oral: 20 mg/kg/dose 3 times daily for 5 days; maximum dose: 400 mg/dose (Bradley 2015; DHHS [pediatric] 2013)

Children and Adolescents ≥12 years:

Non-HIV-exposed/-positive: Oral: 200 mg every 4 hours while awake (5 times daily) for 5 days, or 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])

HIV-exposed/-positive: Adolescents: Oral: 400 mg 3 times daily for 5 to 14 days (DHHS [adult] 2017)

Suppression, chronic:

Non-HIV-exposed/-positive:

Children <12 years: Limited data available: Oral: 20 mg/kg/dose twice daily; maximum dose: 400 mg/dose (Bradley 2015)

Children and Adolescents ≥12 years: Oral: 400 mg twice daily; reassess therapy after 12 months (CDC [Workowski 2015]; Red Book [AAP 2015])

HIV-exposed/-positive:

Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose (DHHS [pediatric] 2013)

Adolescents: Oral: 400 mg twice daily (DHHS [adult] 2017)

HSV gingivostomatitis:

Non-HIV-exposed/-positive: Primary infection:

AAP recommendations: Children and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; usual maximum dose: 200 mg/dose, others have reported higher (400 mg/dose) (Bradley 2015; Cernik, 2008; Red Book [AAP 2015])

Alternate dosing: Infants ≥10 months, Children, and Adolescents: Oral: 15 mg/kg/dose five times daily for 7 days; maximum dose: 200 mg/dose (Amir 1997; Balfour 1999); dosing based on a placebo controlled trial in children 1 to 6 years of age (n=72, treatment group: n=31); results showed when treatment started within 72 hours of symptom onset a shorter duration of symptoms and viral shedding was observed (Amir 1997)

HIV-exposed/-positive (DHHS [pediatric] 2013):

Mild, symptomatic: Oral: Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 400 mg/dose

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

HSV, herpes labialis (cold sore) (HIV-exposed/-positive): Treatment:

Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 5 days; maximum dose: 400 mg/dose (DHHS [pediatric] 2013)

Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (DHHS [adult] 2017)

HSV, herpes labialis (cold sore) recurrent, chronic suppressive therapy: Immunocompetent Children and Adolescents: Oral: 10 mg/kg/dose 3 times daily; maximum daily dose: 1,000 mg/day; reevaluate after 12 months (Red Book [AAP 2015])

HSV mucocutaneous infection:

Immunocompetent host: Infants, Children, and Adolescents:

Treatment (Bradley 2015):

IV: 5 mg/kg/dose every 8 hours

Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; maximum dose: 800 mg/dose

Suppression, chronic: Limited data available; no pediatric data; some experts recommend oral 20 mg/kg/dose 2 to 3 times daily for 6 to 12 months, then reevaluate need; maximum dose: 400 mg/dose (Bradley 2015)

Immunocompromised host:

Treatment:

IV:

Infants and Children: 10 mg/kg/dose every 8 hours for 7 to 14 days (Red Book [AAP 2015])

Adolescents: 5 to 10 mg/kg/dose every 8 hours; change to oral therapy (ie, 400 mg 3 times daily) after lesions begin to regress (DHHS [adult] 2017; Red Book [AAP 2015])

Oral: Children ≥2 years and Adolescents: 1,000 mg/day 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 2009; Red Book [AAP 2015])

Suppression, chronic (cutaneous, ocular) episodes:

Infants and Children (HIV-exposed/-positive): Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose; reassess after 12 months (DHHS [pediatric] 2013)

Children 12 years of age (non-HIV-exposed/-positive): Prevention of ocular episodes: Oral: 400 mg twice daily; reassess at 12 months (Red Book [AAP 2015])

Adolescents (independent of HIV status): Oral: 400 mg twice daily; reassess at 12 months (DHHS [adult] 2017; Red Book [AAP 2015])

HSV progressive or disseminated infection, treatment (immunocompromised host):

Non-HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Red Book [AAP 2015])

HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up to 20 mg/kg/dose) may be used in children <12 years of age (DHHS [pediatric] 2013; Red Book [AAP 2015])

HSV, acute retinal necrosis, treatment (HIV-exposed/-positive): Children (DHHS [pediatric] 2013):

Initial treatment: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days. Note: Follow up IV therapy with oral acyclovir or valacyclovir maintenance therapy.

Maintenance treatment: Begin after 10 to 14 day course of IV acyclovir: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks

HSV prophylaxis; immunocompromised hosts, seropositive:

Hematopoietic stem cell transplant (HSCT) in seropositive recipient (Tomblyn, 2009):

Prevention of early reactivation: Note: Begin at conditioning and continue until engraftment or resolution of mucositis; whichever is longer (~30 days post-HSCT)

Infants, Children, and Adolescents <40 kg:

IV: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours; maximum daily dose: 80 mg/kg/day

Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum dose: 800 mg/dose twice daily

Children and Adolescents ≥40 kg:

IV: 250 mg/m2/dose every 12 hours

Oral: 400 to 800 mg twice daily

Prevention of late reactivation: Note: Treatment during first year after HSCT.

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

Children and Adolescents ≥40 kg: Oral: 800 mg twice daily

Other immunocompromised hosts who are HSV seropositive:

IV: Infants, Children, and Adolescents: 5 mg/kg/dose every 8 hours during period of risk (Red Book [AAP 2015])

Oral: Children ≥2 years and Adolescents: 200 mg every 4 hours while awake (5 doses daily) or 200 mg every 8 hours; administer during periods of risk (Red Book [AAP 2015])

Varicella (chickenpox) or Herpes zoster (shingles), prophylaxis

Hematopoietic stem cell transplant (HSCT): Prophylaxis of disease reactivation: Note: Continue therapy for 1 year after HSCT (Tomblyn 2009):

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

Children and Adolescents ≥40 kg: Oral: 800 mg twice daily

HIV-exposed/-positive: Limited data available: Note: Consider use if >96 hours postexposure or if VZV-immune globulin is not available; begin therapy 7 to 10 days after exposure; some experts begin therapy at first appearance of rash (DHHS [pediatric] 2013)

Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose (DHHS [pediatric] 2013)

Adolescents: Oral: 800 mg 5 times daily for 5 to 7 days (DHHS [adult] 2017)

Other immunocompromised hosts: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose. Note: Consider use if VZV-immune globulin or IVIG is not available; begin therapy 7 to 10 days after exposure (Red Book [AAP] 2015).

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

Immunocompetent host:

Ambulatory therapy: Oral: Children ≥2 years and Adolescents: 20 mg/kg/dose 4 times daily for 5 days; maximum daily dose: 3,200 mg/day (Red Book [AAP 2015])

Hospitalized patient: IV: Infants, Children, and Adolescents: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 14 days (Bradley 2015; Red Book [AAP 2015]); some experts recommend 15 to 20 mg/kg/dose for severe disseminated or CNS infection (Bradley 2015)

Immunocompromised host (non-HIV-exposed/-positive): IV:

Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2015])

Children 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 2015])

HIV-exposed/-positive:

Mild, uncomplicated disease and no or moderate immune suppression: Oral:

Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days and until no new lesions for 48 hours; maximum dose: 800 mg/dose (DHHS [pediatric] 2013)

Adolescents: 800 mg 5 times daily for 5 to 7 days (DHHS [adult] 2017)

Severe, complicated disease or severe immune suppression: IV:

Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days and until no new lesions for 48 hours (DHHS [pediatric] 2013)

Children: 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 (DHHS [pediatric] 2013)

Adolescents: 10 to 15 mg/kg/dose every 8 hours for 7 to 10 days; may convert to oral therapy after defervescence and if no evidence of visceral involvement is evident (DHHS [adult] 2017)

Dosing: Renal Impairment

Note: Monitor closely for neurotoxicity (Chowdhury 2016)

Oral: Children, Adolescents and Adults:

CrCl >25 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl 10 to 25 mL/minute/1.73 m2: If the usual recommended dose is 800 mg 5 times daily: Administer 800 mg every 8 hours

CrCl <10 mL/minute/1.73 m2:

If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours

If the usual recommended dose is 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):

Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions. Administer after hemodialysis on dialysis days.

If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours

If the usual recommended dose is 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)

Alternate dosing (Golightly 2013): Adults:

GFR >50 mL/minute: No dosage adjustment necessary.

GFR 10 to 50 mL/minute: 200 to 800 mg every 8 hours

IV:

CrCl >50 mL/minute/1.73 m2: No dosage adjustment necessary.

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

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

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

Alternate dosing (Golightly 2013):

GFR >50 mL/minute: No dosage adjustment necessary.

GFR 10 to 50 mL/minute: 5 to 10 mg/kg every 12 to 24 hours

GFR <10 mL/minute: 2.5 to 5 mg/kg every 24 hours

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

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

Continuous renal replacement therapy (CRRT) (Heintz 2009): 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.

Dosing: Hepatic Impairment

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

Dosing: Obesity

IV: In obese patients, acyclovir IV has been dosed using ideal body weight (IBW) to avoid overdosing and subsequent toxicity. However, in a pharmacokinetic study using a single acyclovir IV dose, morbidly obese patients (BMI ≥ 40 kg/m2) dosed using IBW had lower systemic exposures compared to normal weight subjects dosed using actual body weight (exposure based on AUC, Cmax, and T > IC50 [time the drug concentration remains above the 50% inhibitory concentration]) (Turner 2016). Therefore, to avoid potentially underdosing obese patients who are severely ill (eg, HSV encephalitis), some clinicians use adjusted body weight (AjBW) to determine the IV dose (AjBW=IBW + [0.4 x (actual body weight-IBW)]) (Wong 2017), although this approach has not been evaluated in clinical studies.

Reconstitution

Powder for injection: Reconstitute acyclovir 500 mg powder with SWFI 10 mL (final concentration 50 mg/mL); do not use bacteriostatic water containing benzyl alcohol or parabens.

For intravenous infusion, dilute reconstituted powder for injection or solution for injection in D5W or NS to a final concentration ≤7 mg/mL. Concentrations >10 mg/mL increase the risk of phlebitis.

Administration

Oral: Administer with or without food.

IV: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Do not administer IM or SubQ. Acyclovir IV is an irritant (depending on concentration); avoid extravasation.

Dietary Considerations

Some products may contain sodium.

Storage

Capsule, oral suspension, tablet: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F); protect from capsule and tablet from moisture.

Powder for injection: Store undiluted vials at 15°C to 25°C (59°F to 77°F). Following reconstitution (final concentration 50 mg/mL), solution is stable for 12 hours at room temperature.

Solution for injection: Store solution at 20°C to 25°C (68°F to 77°F).

Do not refrigerate reconstituted solutions or solutions diluted for infusion as they may precipitate. Once diluted for infusion with NS or D5W, use within 24 hours.

Drug Interactions

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

Adverse Reactions

Oral:

>10%: Central nervous system: Malaise (≤12%)

1% to 10%:

Central nervous system: Headache (≤2%)

Gastrointestinal: Nausea (2% to 5%), vomiting (≤3%), diarrhea (2% to 3%)

Parenteral:

1% to 10%:

Dermatologic: Hives (2%), itching (2%), rash (2%)

Gastrointestinal: Nausea/vomiting (7%)

Hepatic: Liver function tests increased (1% to 2%)

Local: Inflammation at injection site or phlebitis (9%)

Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure

All forms: <1% (Limited to important or life-threatening): Abdominal pain, aggression, agitation, anemia, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, disseminated intravascular coagulopathy (DIC), dizziness, dysarthria, encephalopathy, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, lymphadenopathy, mental depression, myalgia, neutrophilia, pain, psychosis, renal failure, renal pain, seizure, somnolence, sore throat, thrombocytopenia, thrombotic microangiopathy, thrombocytosis, visual disturbances

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Neurotoxicity (eg, tremor/myoclonus, confusion, agitation, lethargy, hallucination, impaired consciousness) has been reported; risk may be increased with higher doses and in patients with renal failure. Monitor patients for signs/symptoms of neurotoxicity; ensure appropriate dosage reductions in patients with renal impairment (Chowdhury 2016).

• Extravasation: Acyclovir IV is an irritant (depending on concentration); avoid extravasation.

• Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, preexisting renal disease, and nephrotoxic drugs increase risk; ensure patient is adequately hydrated during oral or IV therapy.

• Thrombotic microangiopathy: Has been reported in immunocompromised patients receiving acyclovir.

Disease-related concerns:

• Renal impairment: Use with caution; dosage adjustment recommended. Neurotoxicity may be more common in patients with renal impairment (Chowdhury 2016).

• Varicella: Appropriate use: For maximum benefit, treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella but may be effective in patients at increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Injection: Use IV preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia. Encephalopathic changes characterized by lethargy, obtundation, confusion, hallucination, tremors, agitation, seizure, or coma have been observed in patients receiving IV acyclovir.

Other warnings/precautions:

• Adequate hydration: Maintain adequate hydration during oral or IV therapy.

Monitoring Parameters

Urinalysis, BUN, serum creatinine, urine output; liver enzymes, CBC; monitor for neurotoxicity and nephrotoxicity in pediatric patients when using high dose therapy; neutrophil count at least twice weekly in neonates receiving acyclovir 60 mg/kg/day IV. Monitor infusion site.

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects were not observed in animal reproduction studies. Acyclovir has been shown to cross the human placenta (Henderson 1992). Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Acyclovir is recommended for the treatment of genital herpes in pregnant women (CDC [Workowski 2015]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, dizziness, fatigue, loss of strength and energy, or injection site irritation. Have patient report immediately to prescriber behavioral changes, mood changes, confusion, hallucinations, seizures, tremors, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; severe loss of strength and energy; dark urine or jaundice; pale skin; change in the amount of urine passed; vision changes; change in strength on one side is greater than the other; difficulty speaking or thinking; change in balance; or fever) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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