Acyclovir

Acyclovir is an Antiviral Agent belonging to the Pharmacology class of Guanosine analog.

Acyclovir is used in the treatment of Bell palsy, new onset, Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients, Herpes simplex virus, central nervous system infection; Herpes simplex virus, mucocutaneous infection; Herpes simplex virus, prevention in immunocompromised patients; Herpes zoster, treatment ;Herpes zoster ophthalmicus Varicella, treatment Varicella zoster virus, acute retinal necrosis ;Varicella zoster virus, encephalitis ;Varicella zoster virus, prevention in immunocompromised patients

Acyclovir is poorly absorbed from the gastrointestinal tract which gets penetrates into the skin. With bioavailability of 10-20% (oral) and widely get distributed to body tissues including CSF (approx 50% of plasma levels) and crosses the placenta and enters the breast milk with volume of distribution: 0.7 L/kg. Plasma protein binding: 9-33% which gets converted by viral enzymes to Acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymesand get excreted via urine (62-91% as unchanged drug and 9-14% as metabolites). With elimination half-life of approx 2-3 hours.

Acyclovir is available in the form of dosage forms as Capsule, IV Solution, Suspension, Tablet, Cream, Ointment.

Acyclovir is available in India, France, Japan, and the USA.

Acyclovir is converted to Acyclovir monophosphate by virus-specific thymidine kinase then further converted to Acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate competes with deoxyguanosine triphosphate for viral DNA polymerase and incorporates into viral DNA to block DNA synthesis and viral replication.

Acyclovir is available in the form of Capsule, IV Solution, Suspension, Tablet, Cream, Ointment.

Acyclovir is used in the treatment of Bell palsy, new onset, Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients, Herpes simplex virus, central nervous system infection; Herpes simplex virus, mucocutaneous infection; Herpes simplex virus, prevention in immunocompromised patients; Herpes zoster, treatment ;Herpes zoster ophthalmicus Varicella, treatment Varicella zoster virus, acute retinal necrosis ;Varicella zoster virus, encephalitis ;Varicella zoster virus, prevention in immunocompromised patients

Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase.Acyclovir triphosphate has higher affinity for viral DNA polymerase than cellular DNA polymerase and incorporates into the DNA where the missing 2' and 3' carbons causes DNA chain termination.

Acyclovir is approved for use in the following clinical indications:

Herpes simplex virus (HSV), genital:

Treatment of initial episodes and the management of recurrent episodes of genital herpes.

Herpes zoster (shingles):

Acute treatment of herpes zoster (shingles).

Varicella (chickenpox):

Treatment of varicella (chickenpox).

Herpes simplex encephalitis:

Treatment of herpes simplex encephalitis.

Herpes virus:

Buccal tablet: Treatment of recurrent herpes labialis (cold sores) in immunocompetent adults

Cream: Treatment of recurrent herpes labialis (cold sores) in immunocompetent children ≥12 years of age, adolescents, and adults

Ointment: Management of initial genital herpes and in limited non-life-threatening mucocutaneous herpes simplex virus infections in immunocompromised patients. Note: The CDC discourages topical antiviral therapy for genital herpes infection due to minimal clinical benefit.

Herpetic keratitis:

Treatment of acute herpetic keratitis (dendritic ulcers) in patients with herpes simplex (HSV-1 and HSV-2) virus.

Although not approved there have been certain off labelled uses documented for Acyclovir which includes:

• Bell palsy, new onset
• Cytomegalovirus prevention in low-risk allogeneic hematopoietic cell transplant recipients
• Herpes simplex virus, esophagitis
• Herpes simplex virus, prevention in immunocompromised patients
• Herpes zoster ophthalmicus
• Varicella zoster virus, acute retinal necrosis
• Varicella zoster virus, encephalitis
• Varicella zoster virus, prevention in immunocompromised patients.

Bell palsy, new onset (adjunctive therapy) (alternative agent) (off-label use): Oral: 400 mg 5 times daily for 10 days in combination with corticosteroids; begin within 3 days of symptom onset. Note: Antiviral therapy alone is not recommended; some experts only recommend addition of an antiviral to steroid therapy in patients with severe Bell palsy.

Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients (alternative agent) (off-label use): Note: Begin at engraftment and continue to day 100; requires close monitoring for cytomegalovirus (CMV) reactivation (due to weak activity); not for use in patients at high risk for CMV disease:

IV: 500 mg/m²/dose every 8 hours for up to 4 weeks or until hospital discharge, followed by oral therapy.

Oral: Following initial IV therapy: 800 mg 4 times daily .

Herpes simplex virus, central nervous system infection (encephalitis or meningitis): IV: 10 mg/kg/dose every 8 hours. Duration for encephalitis is 14 to 21 days and for meningitis is 10 to 14 days; treatment of encephalitis requires IV therapy while treatment of meningitis may include step-down oral antiviral therapy. Note: Empiric herpes simplex virus (HSV) therapy should be initiated in all patients with suspected encephalitis.

Herpes simplex virus, mucocutaneous infection:

Esophagitis (off-label use):

Immunocompetent patients: Oral: 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days.

Immunocompromised patients: Oral: 400 mg 5 times daily for 14 to 21 days.

Patients with severe odynophagia or dysphagia: IV: 5 mg/kg/dose every 8 hours; patients who rapidly improve can be switched to an oral antiviral to complete a total of 7 to 14 days of therapy.

Genital:

Immunocompetent patients:

Treatment, initial episode:

Oral: 400 mg 3 times daily for 7 to 10 days; extend duration if lesions have not healed completely after 10 days.

IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; once clinically improved, may switch to oral antiviral therapy to complete >10 days of therapy total.

Treatment, recurrent episode: Oral: 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days. Note: Treatment is most effective when initiated during the prodrome or within 1 day of lesion onset .

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily. Note: Reassess need periodically (eg, annually) .

Immunocompromised patients (including patients with HIV):

Treatment, initial or recurrent episode:

Oral: 400 mg 3 times daily for 5 to 10 days (7 to 10 days for initial episode in patients with HIV); extend treatment duration if lesions have not healed completely after 10 days .

IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; may transition to oral antiviral therapy once lesions begin to regress and continue for >10 days of therapy and until complete resolution .

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 to 800 mg 2 to 3 times daily. Note: Reassess need periodically (eg, annually).

Pregnant patients:

Treatment, initial episode: Oral: 400 mg 3 times daily for 7 to 10 days; extend treatment duration if lesion has not healed completely after 10 days .

Treatment, recurrent episode (symptomatic): Oral: 400 mg 3 times daily or 800 mg twice daily for 5 days. Note: Some experts reserve treatment of recurrent episodes for patients with severe and/or frequent symptoms.

Treatment, severe or disseminated disease: IV: 5 to 10 mg/kg every 8 hours for 2 to 7 days, then change to oral therapy for primary infection to complete 10 days of therapy.

Suppressive therapy, for patients with a genital HSV lesion anytime during pregnancy: Oral: 400 mg 3 times daily, beginning at 36 weeks gestation and continued until delivery; some experts recommend discontinuing suppressive therapy at the onset of labor . Note: For patients with a primary infection during the third trimester, may consider suppressive therapy earlier than 36 weeks' gestation.

Orolabial: Note: Initiate therapy at earliest symptom.

Immunocompetent and immunocompromised patients (including patients with HIV):

Treatment, initial or recurrent episode:

Oral: 400 mg 3 times daily for 5 to 10 days and until complete lesion resolution in immunocompromised patients.

IV (for severe disease in immunocompromised patients): 5 mg/kg/dose every 8 hours; switch to oral acyclovir (or similar antiviral) once lesions begin to regress and continue until complete resolution .

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily. Note: Reassess need periodically (eg, annually)

Herpes simplex virus, prevention in immunocompromised patients (off-label use):

Seropositive hematopoietic cell transplant recipients (allogeneic or autologous) or seropositive patients undergoing leukemia induction chemotherapy:

IV: 250 mg/m²/dose every 12 hours

Oral: 400 to 800 mg twice daily

Note: Initiate with the chemotherapeutic or conditioning regimen and continue until recovery of WBC count and resolution of mucositis; duration may be extended in patients with frequent recurrences or graft-vs-host disease .

Solid organ transplant recipients (HSV-seropositive patients who do not require CMV prophylaxis): Oral: 400 to 800 mg twice daily for ≥1 month ; some experts recommend continuing for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection.

Herpes zoster (shingles), treatment:

Note: Initiate at earliest sign or symptom. Antiviral treatment is most effective ≤72 hours after rash onset but may be initiated >72 hours in certain situations (eg, new lesions continue to appear); for immunocompromised patients, initiate treatment even if >72 hours after symptom onset unless all lesions have crusted .

Acute localized dermatomal lesion(s): Oral: 800 mg 5 times daily for 7 to 10 days; for slowly improving lesions, may extend therapy until resolution . For select immunocompromised patients at high risk of dissemination (eg, recent transplant, graft-versus-host disease), some experts suggest regimens used for disseminated zoster.

Disseminated zoster (extensive cutaneous lesions or visceral involvement): IV: 10 mg/kg/dose every 8 hours. When formation of new lesions has ceased and signs/symptoms of visceral infection are improving, switch to an oral antiviral to complete a total of 10 to 14 days of therapy

Herpes zoster ophthalmicus (off-label use):

Immunocompromised patients or patients who require hospitalization for sight-threatening disease: IV: 10 mg/kg/dose every 8 hours for 7 days

Varicella (chickenpox), treatment:

Ideally initiate therapy within 24 hours of symptom onset, but may start later if the patient still has active lesions:

Immunocompetent patients with uncomplicated infection: Oral: 800 mg 5 times daily for ≥5 to 7 days and until all lesions have crusted

Immunocompromised patients (including patients with HIV):

Severe or complicated infection: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days. May switch to oral antiviral after defervescence if no evidence of visceral involvement; continue until all lesions have crusted.

Uncomplicated infection: Oral: 800 mg 5 times daily for 5 to 7 days; some experts recommend a minimum duration of 7 days, extending the course until all lesions have crusted

Varicella zoster virus, acute retinal necrosis (off-label use): IV:

10 mg/kg/dose every 8 hours for 10 to 14 days, followed by ~6 weeks of valacyclovir ; in patients with HIV, intravitreal ganciclovir should be added

Varicella zoster virus, encephalitis (off-label use): IV:

10 mg/kg/dose every 8 hours; some experts use higher doses, up to 15 mg/kg/dose every 8 hours, although tolerability may be a limiting factor. The duration is 10 to 14 days.

Varicella zoster virus, prevention in immunocompromised patients (off-label use):

Seropositive hematopoietic cell transplant recipients (allogeneic and autologous): Oral: 800 mg twice daily . Note: Initiate with the chemotherapeutic or conditioning regimen and continue for 1 year; may extend duration in patients requiring ongoing immunosuppression (some experts continue prophylaxis in these patients until 6 months after discontinuation of all systemic immunosuppression).

Solid organ transplant recipients (VZV-seropositive patients who do not require CMV prophylaxis): Oral: 200 mg 3 to 5 times daily for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection

Acyclovir is available in various dosage strengths as 200 mg, 50 mg/ml, 200 mg/ 5ml, 400 mg, 800 mg.

Acyclovir is available in the form of Capsule, IV Solution, suspension, Tablet, Ointment.

Dose Adjustment in Kidney patient

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m²): IV, Oral: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients.

Use the indication-specific maximum allowable dose along with therapeutic drug monitoring when available.

Hemodialysis, intermittent (thrice weekly): Dialyzable (60% reduction following a 6-hour session). Therapeutic drug monitoring of acyclovir is recommended when available.

Oral:

If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours. Administer after dialysis when given on a dialysis day or administer an additional dose after each dialysis .

If the usual recommended dose is 800 mg 5 times daily: Administer a loading dose of 400 mg, followed by a maintenance dose of 200 mg every 12 hours, plus an additional 400 mg dose after each dialysis session. Note: Dose based on pharmacokinetic data and computer modeling.

IV: 2.5 to 5 mg/kg/dose every 24 hours. Administer after dialysis when given on a dialysis day. Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.

Peritoneal dialysis:

Dialyzable (12% reduction during continuous ambulatory peritoneal dialysis): Therapeutic drug monitoring of acyclovir is recommended when available.

Oral:

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 600 to 800 mg every 24 hours.

IV: 2.5 to 5 mg/kg/dose every 24 hours, no supplemental dose needed. Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available .

IV: 5 to 10 mg/kg/dose every 12 to 24 hours. Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.

PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available .

IV: 5 to 10 mg/kg/dose every 12 to 24 hours. On non-PIRRT days, dose as for CrCl <10 mL/minute/1.73 m². Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.

Dose Adjustment in Hepatic Impairment Patient:

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

Dose Adjustment in the Pediatric patient:

Cytomegalovirus (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:

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.

Varicella zoster virus, acute retinal necrosis, treatment, HIV-exposed/-infected:

Initial treatment: Note: Follow up IV therapy with oral valacyclovir or acyclovir therapy (valacyclovir preferred).

Infants and Children: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days .

Adolescents: IV: 10 mg/kg/dose every 8 hours for 10 to 14 days; recommended to be used in combination with 1 to 2 doses of intravitreal ganciclovir.

Maintenance treatment (alternative to valacyclovir): Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks to begin after 10- to 14-day course of IV acyclovir.

Herpes zoster (shingles), treatment:

Immunocompetent host:

Ambulatory therapy: Children ≥12 years and Adolescents: Oral: 800 mg every 4 hours (5 doses per day) for 5 to 7 days.

Hospitalized patient:

Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days.

Children ≥2 years and Adolescents: IV: 500 mg/m²/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose every 8 hours.

Immunocompromised host, non-HIV-exposed/-infected: IV: Infants, Children, and Adolescents: 10 mg/kg/dose every 8 hours for 7 to 10 days.

HIV-exposed/-infected:

Mild, uncomplicated disease and no or moderate immune suppression:

Infants and Children: Oral: 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.

Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 7 to 10 days, longer if lesions resolve slowly.

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

Infants: IV: 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.

Children: IV: 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.

Adolescents: IV: 10 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.

Herpes simplex virus (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.

Chronic suppressive therapy following any neonatal HSV infection: 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.

Herpes simplex virus encephalitis, treatment:

Independent of HIV status:

Infants and Children 3 months to <12 years: 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 routinely recommended.

Children ≥12 years and Adolescents: IV: 10 mg/kg/dose every 8 hours for 14 to 21 days.

Herpes simplex virus, genital infection:

First infection, mild to moderate:

Non-HIV-exposed/-infected:

Children <12 years: Oral: 40 to 80 mg/kg/day divided in 3 to 4 doses per day for 7 to 10 days; maximum daily dose: 1,200 mg/day.

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.

HIV-exposed/-infected:

Children: Oral: 20 mg/kg/dose 3 times daily for 7 to 10 days; maximum dose: 400 mg/dose.

Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days.

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.

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.

Children and Adolescents ≥12 years:

Non-HIV-exposed/-infected: 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.

HIV-exposed/-infected: Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days.

Suppression, chronic:

Non-HIV-exposed/-infected:

Children <12 years: Limited data available: Oral: 20 mg/kg/dose twice daily; maximum dose: 400 mg/dose. Children and Adolescents ≥12 years: Oral: 400 mg twice daily; reassess therapy after 12 months.

HIV-exposed/-infected:

Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose.

Adolescents: Oral: 400 mg twice daily .

HSV orolabial disease (ie, gingivostomatitis, herpes labialis):

Non-HIV-exposed/-infected: Primary infection: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; usual maximum dose: 800 mg/dose.

HIV-exposed/-infected

Mild, symptomatic:

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

Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days.

Moderate to severe, symptomatic: Note: Switch to oral therapy once lesions begin to regress and continue oral therapy until lesions completely healed.

Infants and Children: IV: 5 to 10 mg/kg/dose every 8 hours.

Adolescents: IV: 5 mg/kg/dose every 8 hours.

Herpes simplex virus, mucocutaneous infection:

Immunocompetent host: Infants, Children, and Adolescents:

Treatment:

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 revaluate need; maximum dose: 400 mg/dose.

Immunocompromised host:

Treatment:

IV:

Infants and Children: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days.

Adolescents: IV: 5 to 10 mg/kg/dose every 8 hours; change to oral therapy after lesions begin to regress.

Oral: Children ≥2 years and Adolescents: 1,000 mg/day in 3 to 5 divided doses for 7 to 14 days.

Suppression, chronic (cutaneous, ocular) episodes:

Non-HIV-exposed/-infected:

Children ≥12 years and Adolescents: Oral: 400 mg twice daily; reassess at 12 months.

HIV-exposed/-infected:

Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose; reassess after 12 months

Adolescents: Oral: 400 mg twice daily; reassess at 12 months

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

Non-HIV-exposed/-infected: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days

HIV-exposed/-infected: 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

HSV, acute retinal necrosis, treatment, HIV-exposed/-infected:

Infants and Children:

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 (alternative to valacyclovir): 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:

HSCT in seropositive recipient:

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.

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.

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

HSCT: Prophylaxis of disease reactivation: Note: Continue therapy for 1 year after HSCT.

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/-infected: 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

Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose.

Adolescents: Oral: 800 mg 5 times daily for 5 to 7 days.

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.

Varicella (chickenpox), treatment:

Begin treatment within the first 24 hours of rash onset:

Immunocompetent host:

Ambulatory therapy: Oral: Infants, Children, and Adolescents: 20 mg/kg/dose 4 times daily for 5 days; maximum daily dose: 3,200 mg/day.

Hospitalized patient: IV: Infants, Children, and Adolescents: 10 mg/kg/dose or 500 mg/m²/dose every 8 hours for 7 to 14 days ; some experts recommend 15 to 20 mg/kg/dose for severe disseminated or CNS infection .

Immunocompromised host, non-HIV-exposed/-infected:

Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours; duration dependent upon clinical response, typically 7 to 14 days.

Children ≥2 years and Adolescents: IV: 500 mg/m²/dose every 8 hours duration dependent upon clinical response, typically 7 to 14 days; some experts recommend 10 mg/kg/dose every 8 hours.

HIV-exposed/-infected:

Mild, uncomplicated disease and no or moderate immune suppression:

Infants and Children: Oral: 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.

Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 5 to 7 days.

Severe, complicated disease or severe immune suppression:

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

Children: IV: 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.

Adolescents: IV: 10 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.

Dosage adjustment for concomitant therapy:

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Monitor closely for neurotoxicity.

Infants, Children and Adolescents: IV:

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

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

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

CrCl <10 mL/minute/1.73 m²: Administer 50% of the usual recommended dose every 24 hours (eg, if the usual recommended dose is 10 mg/kg/dose every 8 hours, then administer 5 mg/kg/dose every 24 hours)

Intermittent hemodialysis (IHD): Dialyzable (60% reduction following a 6-hour session): 5 mg/kg/dose every 24 hours; administer after hemodialysis on dialysis days

Peritoneal dialysis (PD): 5 mg/kg/dose every 24 hours; no supplemental dose needed

Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 hour.

May be taken with or without food. May be taken w/ meals to reduce GI discomfort.

Acyclovir may be contraindicated in the following:

Hypersensitivity to Acyclovir and similar antivirals.

Concerns related to adverse effects:

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

Disease-related concerns:

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).

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.

Acyclovir is present in breast milk.

Acyclovir use for the treatment of labial herpes simplex in a lactating patient 6 weeks postpartum was described in a case report. Acyclovir 900 mg IV was administered daily for 5 days and breast milk was sampled every 6 hours after the last dose. The maximum breast milk concentration was 7.3 mcg/mL observed within the first 72 hours of sampling (Bork 1995). Using a milk concentration of 7.3 mcg/mL, the relative infant dose (RID) of acyclovir is 1.83% to 3.65% compared to an IV infant therapeutic dose of 30 to 60 mg/kg/day, providing an estimated infant dose via breast milk of 1.095 mg/kg/day. In general, breastfeeding is considered acceptable when the RID of a medication is <10%

• The mean half-life of acyclovir in breast milk was 3.2 hours in one study
• Low/negligible concentrations of acyclovir appear in breast milk for up to 5 days after the last maternal dose.

Patients with HSV infection taking acyclovir may breastfeed as long as there are not lesions on the breast, body lesions are covered, and strict hand hygiene is practiced; patients with herpetic lesions near or on the breast should not breastfeed. Patients with breast lesions can pump and discard milk to maintain milk supply until lesions are healed and breastfeeding can be resumed.

Some products may contain sodium.

The adverse reactions related to molecule Acyclovir can be categorized as:

• Common Adverse effects:

Contact sensitisation (topical). Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain.

• Less Common adverse effect:

Increased liver enzymes (reversible), BUN and creatinine. Nervous system disorders: Headache, dizziness. Skin and subcutaneous tissue disorders: Pruritus, rash, photosensitivity, urticaria, accelerated diffuse hair loss. Vascular disorders: Phlebitis (IV).

• Rare adverse effects:

Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (immunocompromised patients). Renal failure

The clinically relevant drug interactions of Acyclovir are briefly summarized here:

• Probenecid, cimetidine and mycophenolate mofetil may increase the plasma concentration of Acyclovir.
• May increase the serum concentration of theophylline.
• May increase risk of renal impairment with nephrotoxic drugs.

The common side of Acyclovir include the following:

Contact sensitisation (topical). Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain.

The use of Acyclovir should be prudent in the following group of special populations:

Adults with Impaired Renal Function:

Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure. The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.

Pediatrics:

Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours . Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively. Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours.

Geriatrics:

Acyclovir plasma concentrations are higher in geriatric patients compared with younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment.

Symptoms:

Oral: Nausea, vomiting, headache and confusion. IV: Elevated serum creatinine and BUN, and subsequent renal failure; neurological effects (e.g. confusion, hallucinations, agitation, seizures and coma).

Management:

Ensure adequate hydration to prevent crystal formation in the urine. Consider haemodialysis until renal function is restored.

Pharmacodynamics:

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.

Pharmacokinetics:

Absorption:

Via urine (62-91% as unchanged drug and 9-14% as metabolites). Elimination half-life: Approx 2-3 hours.

• https://www.pfizer.com/products/product-detail/altace
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022021s008lbl.pdf
• https://go.drugbank.com/drugs/DB00178