Dosing

Adult dosing:

Acute retinal necrosis

:
HIV-infected:
10 to 15 mg/kg IV every 8 hours for 10 to 14 days plus ganciclovir 2 mg/0.05 mL intravitreally twice weekly for 1 to 2 doses, followed by valacyclovir 1 g orally 3 times daily for 6 weeks (guideline

dosage

)
1500 mg/m(2)/day IV for 7 to 10 days followed by oral

acyclovir

for 2 to 4 weeks (off-label

dosage

)

Encephalitis due to human

herpes simplex

virus:

10 mg

/kg IV (over 1 hour) given every 8 hours for 10 days
Maximum

20 mg

/kg every 8 hours (FDA

dosage

)
5 to

10 mg

/kg IV every 8 hours for 21 days (guideline

dosage

)

Genital

herpes simplex

, severe initial clinical episodes, immunocompetent patients:
5 mg/kg IV over 1 hour every 8 hours for 5 days
Maximum dose,

20 mg

/kg every 8 hours (FDA

dosage

)
5 to

10 mg

/kg IV every 8 hours for 2 to

7 days

or until clinical improvement occurs, and then switch to oral therapy to complete at least 10 days of total therapy (guideline

dosage

)

Herpes simplex

, Mucosal and cutaneous – Patient immunocompromised:
5 mg/kg IV (over 1 hour) given every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (FDA

dosage

)

Severe infections in HIV-infected patients:
5 mg/kg IV every 8 hours (guideline

dosage

)

Herpes simplex

– Viral hepatitis:
5 to

10 mg

/kg IV every 8 hours for 2 to

7 days

or until clinical improvement occurs, and then switch to oral therapy to complete at least 10 days of total therapy (guideline

dosage

)

Herpes zoster

, Shingles – Patient immunocompromised:

10 mg

/kg IV (over 1 hour) given every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (FDA

dosage

)

Extensive cutaneous or visceral involvement, HIV-infected patients:
10 to 15 mg/kg IV every 8 hours until clinical improvement, then switch to oral therapy for a total duration of 10 to 14 days
Oral options include valacyclovir 1 g 3 times daily, famciclovir 500 mg 3 times daily, or

acyclovir

800 mg 5 times daily (guideline

dosage

)

HIV infection

– Varicella:
Severe or complicated cases:
10 to 15 mg/kg IV every 8 hours for 7 to 10 days (guideline

dosage

)

Pediatric dosing:
Congenital

herpes simplex

:
Birth to 3 months of age:

10 mg

/kg IV (over 1 hour) given every 8 hours for 10 days; doses of 15 to

20 mg

/kg IV have been used; Maximum

20 mg

/kg every 8 hours (FDA

dosage

)

Infants:
Disseminated and CNS disease:

20 mg

/kg IV every 8 hours for 21 days (guideline

dosage

)
Skin and mucous membrane disease:

20 mg

/kg IV every 8 hours for 14 days (guideline

dosage

)

Encephalitis due to human

herpes simplex

virus:
3 months to

12 years

of age:

20 mg

/kg IV (over 1 hour) given every 8 hours for 10 days
Maximum

20 mg

/kg every 8 hours

12 years

of age and older:

10 mg

/kg IV (over 1 hour) given every 8 hours for 10 days
Maximum

20 mg

/kg every 8 hours

Genital herpes

simplex, severe initial clinical episodes, immunocompetent patients:

12 years

or older:
5 mg/kg IV (over 1 hour) given every 8 hours for 5 days
Maximum

20 mg

/kg every 8 hours

Herpes simplex

, Mucosal and cutaneous – Patient immunocompromised:
Younger than

12 years

:

10 mg

/kg IV (over 1 hour) every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (FDA

dosage

)

12 years

or older:
5 mg/kg IV (over 1 hour) every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (FDA

dosage

)

Moderate to severe gingivostomatitis in HIV-infected patients:
5 to

10 mg

/kg IV 3 times daily (guideline

dosage

)

Herpes zoster

, Shingles – Patient immunocompromised:
Severe immunosuppression, trigeminal nerve involvement, or extensive multidermatomal zoster, HIV-infected (younger than

12 years

of age):

10 mg

/kg IV 3 times daily; switch to oral

acyclovir

once cutaneous lesions and visceral disease are clearly resolving for a total duration of 10 to 14 days (guideline dosing)

Younger than

12 years

of age:

20 mg

/kg IV (over 1 hour) given every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (manufacturer dosing)

12 years

and older:

10 mg

/kg IV (over 1 hour) given every 8 hours for

7 days

Maximum

20 mg

/kg every 8 hours (manufacturer dosing)

HIV infection

– Varicella:
Complicated or severe immunosuppression; CDC immunologic category 3:

10 mg

/kg IV 3 times daily for 7 to 10 days or until no new lesions appear for 48 hours (guideline

dosage

)

Indications

FDA-Labeled Indications:
Congenital

herpes simplex

Encephalitis due to human

herpes simplex

virus
Genital

herpes simplex

, severe initial clinical episodes, immunocompetent patients

Herpes simplex

, Mucosal and cutaneous – Patient immunocompromised

Herpes zoster

, Shingles – Patient immunocompromised

Non-FDA Labeled Indications:

Acute retinal necrosis

Chickenpox pneumonia

Herpes simplex

meningitis

Herpes simplex

–

Viral

hepatitis

Herpes simplex

–

Viral

respiratory infection

Herpes zoster

auricularis

HIV infection

– Varicella
Varicella

Viral

encephalitis

Mechanism of Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against

herpes simplex

virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of

acyclovir

is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV.
This

viral

enzyme converts

acyclovir

into

acyclovir

monophosphate, a nucleotide analogue.
The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes.
In vitro,

acyclovir

triphosphate stops replication of herpes

viral

DNA.
This is accomplished in 3 ways:
1) Competitive inhibition of

viral

DNA polymerase

,
2) Incorporation into and termination of the growing

viral

DNA chain
3) Inactivation of the

viral

DNA polymerase

.
The greater

antiviral

activity of

acyclovir

against HSV compared to VZV is due to its more efficient phosphorylation by the

viral

TK.

Adverse Effect

Common:
Dermatologic:
Injection site inflammation (approximately 9%)

Gastrointestinal:
Nausea
Vomiting

Renal

:
Serum blood urea nitrogen raised, Transient
Serum creatinine raised, Transient

Serious:
Dermatologic:
Stevens-Johnson syndrome
Toxic epidermal necrolysis

Hematologic:
Thrombotic thrombocytopenic purpura

Neurologic:
Neurotoxicity

Renal:

Hemolytic uremic syndrome

Renal

failure

Contraindication

Hypersensitivity to

acyclovir

or valacyclovir

Interaction

Co-administration of probenecid with intravenous

acyclovir

has been shown to increase the mean

acyclovir

half-life and the area under the concentration-time curve. Urinary excretion and

renal

clearance were correspondingly reduced.

Major:
Foscarnet (theoretical)
Tolvaptan (theoretical)

Moderate:
Fosphenytoin (probable)
Phenytoin (probable)
Valproic Acid (probable)

Phamacokinetics

Distribution:
Plasma Protein binding: 9% to 33%

Volume of Distribution (Vd):
Adults: 48 L/m (2) (range 37 to 57 L/m(2))
Birth to 3 months: 1.08 +/- 0.35 L/kg
3 months to 16 years: 1.01 +/- 0.28 L/kg

Metabolism:
Metabolites:
9-carboxymethyl methylguanine: inactive

Excretion:

Renal

: 62% to 91% unchanged

Fecal: 2%

Dialyzable:
Hemodialysis: Yes, 60% decrease in plasma concentrations following 6 hours dialysis period
Peritoneal dialysis: No, less than 10% is removed

Other extracorporeal:
Plasmapheresis: No
Exchange transfusion: No
Hemofiltration: No

Elimination:
Adults: 2.5 hours to 3.5 hours
Anuric adults: 19.5 hours
Pediatrics: 2.36 hours to 3.8 hours

Precaution

Hematologic:
Thrombotic thrombocytopenic purpura and

hemolytic uremic syndrome

, including fatal cases, has been reported in immunocompromised patients.

Neurologic:
Encephalopathic changes (e.g., lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma) have been reported;

use

with caution in patients with underlying neurologic abnormalities, significant hypoxia, or serious

renal

, hepatic, or electrolyte abnormalities.

Renal

:
Impaired

renal

function may occur and is dependent upon rate of administration; risk is increased in patients with pre-existing

renal

disease and dehydration, and with concomitant

use

of other nephrotoxic drugs.
Precipitation of

acyclovir

crystals in

renal

tubules may occur and can result in acute renal failure; accompany administration with adequate hydration.

Renal

failure, including fatal cases, has been reported.

Pregnancy Category

B (FDA)
B3 (AUS)

Breast Feeding

AAP: Maternal medication usually compatible with breastfeeding.

Monitoring

Genital herpes

:
Reduction in the duration of

viral

excretion, new lesion formation, duration of vesicle presence, and promotion of lesion healing are indicative of efficacy.

Herpes simplex encephalitis:
Reduction in signs or

symptoms of

herpes simplex

encephalitis is indicative of efficacy.

herpes simplex

in immunocompromised patients:
Decreased

viral

excretion, reduced pain, and healing of lesions is indicative of efficacy.

Neonatal

herpes simplex

:
Improvement in signs and

symptoms of

herpes simplex

is indicative of efficacy.

Varicella zoster in immunocompromised patients:
Reductions in cutaneous and visceral dissemination are indicative of efficacy.

Renal

function in elderly patients

How to Take or Administration

General Information:
Injection:
Do not administer as a subcutaneous or IM injection

Intravenous:
Do not

use

as a rapid or bolus injection; administer only as an IV infusion

Reconstitute with sterile water for injection and

use

within 12 hours; do not

use

bacteriostatic water for injection containing benzyl alcohol or parabens

Infusion:
After reconstitution, dilute the appropriate dose in D5W or NS to a concentration of 7 mg/mL or less and infuse over 1 hour; biologic or colloidal fluids are not recommended for dilution

Dosage Form

Intravenous Powder for Solution:
500 MG
1000 MG

Intravenous Solution:
50 MG/1 ML

Treatment

Management of Mild to Moderate Toxicity:
Patients generally do well with supportive care. Nausea and vomiting should be treated with antiemetics. Rashes should be treated with supportive care, discontinuation of the offending agent, and consideration of antihistamines and corticosteroids. With massive overdose, hydrate patients and monitor

renal

function.

Management of Severe Toxicity:
Supportive care remains the mainstay of care in severe toxicity. Seizures should be treated with benzodiazepines as first line therapy, followed by barbiturates or propofol, if seizures persist. Hydrate patients and monitor urine output and

renal

function. Airway protection should be employed as need for patients with coma.

Toxicology

A toxic dose has not been established for these agents.

Patient Counselling or Clinical Teaching

Advise patient to maintain adequate hydration to prevent

renal

toxicity.
Drug may cause nausea, vomiting, itching, and rash, hives, or injection site inflammation or phlebitis.
Instruct patient to report signs or

symptoms of

encephalopathic changes (e.g., lethargy, obtundation, tremors, confusion, hallucinations, agitation, or seizures).