ACYCLOVIR (Acyclovir Sodium)

       ACYCLOVIR (Acyclovir Sodium)

ACYCLOVIR (Acyclovir Sodium)

ACYCLOVIR (Acyclovir Sodium)

DESCRIPTION

Acyclovir is a synthetic nucleoside analog active against herpes viruses. Acyclovir sodium sterile powder for 

solution for injection is a formulation for intravenous administration.

The chemical name of acyclovir sodium is 2-amino-1, 9-dihydro-9-[(2-hydroxyethoxy) methyl] - 6H - purin - 6 

- one monosodium salt. 

Acyclovir sodium is a white to off-white, crystalline powder with a molecular weight of 247 daltons, and a 

solubility in water at 25° C exceeding 100 mg/mL. Each 250 mg of acyclovir sodium sterile powder for solution 

for injection when reconstituted with 10 mL of sterile diluent yields 25 mg/mL. Each 500 mg or 1 g vial of 

acyclovir sodium sterile powder for solution for injection when reconstituted with 10 mL or 20 mL, respectively, 

sterile diluent yields 50 mg/mL acyclovir (pH approximately 11). Further dilution in any appropriate intravenous 

solution must be performed before infusion (see DOSAGE AND ADMINISTRATION: Method of Preparation and Administration). At physiologic pH, acyclovir exists as the un-ionized form with a molecular weight of 225 

daltons and a maximum solubility of 2.5 mg/mL in water at 37° C. May contain sodium hydroxide for pH 

adjustment. Acyclovir sodium sterile powder for solution for injection is prepared as a solution and lyophilized in 

its final container. For each 250 mg of acyclovir, the sodium content is approximately 26 mg (1.1 mEq); for each 

500 mg of acyclovir, the sodium content is approximately 52 mg (2.2 mEq).

VIROLOGY

Mechanism of Antiviral 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). In cell culture, acyclovir's highest 

antiviral activity is against HSV-1, followed in decreasing order of potency against HSV-2 and VZV.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidinen 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 three ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation 

into and termination of the growing viral DNA chain, and 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.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical 

response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. 

Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in 

cell culture (IC50), vary greatly depending upon a number of factors.

Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL 

for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and 

clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka 

vaccine strain of VZV with a mean IC50 for 1.35 mcg/mL. 

Drug Resistance

Resistance of HSV and VZV to antiviral nucleoside analogues can result from qualitative or quantitative changes 

in the viral TK or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have 

been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the 

acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, 

other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. 

TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral 

resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with 

normal renal function during Phase I & II studies after single doses ranging from 0.5 to 15 mg/kg and after multiple 

doses ranging from 2.5 to 15 mg/kg every eight hours. Proportionality between dose and plasma levels is seen after 

single doses or at steady state after multiple dosing.

When acyclovir was administered to adults at 5 mg/kg (approximately 250 mg/m 2 ) by 1-hour infusions every 

eight hours, mean steady-state peak and trough concentrations of 9.8 mcg/mL (range: 5.5 to 13.8 mcg/mL) and 

0.7 mcg/mL (range: 0.2 to 1.0 mcg/mL), respectively, were achieved. At a dose of 10 mg/kg given by one-hour 

infusion every eight hours, mean steady-state peak and trough concentrations were 22.9 mcg/mL (range: 14.1 to 

44.1 mcg/mL) and 1.9 mcg/mL (range: 0.5 to 2.9 mcg/mL).

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein 

binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not Pediatrics (under 12 years of age):10 mg/kg infused at a constant rate over at least one hour, every eight hours for seven days.

Method of Preparation

Each 10 mL vial contains acyclovir sodium equivalent to 250 mg or 500 mg of acyclovir. Each 20 mL vial contains 

acyclovir sodium equivalent to 1000 mg of acyclovir. The contents of the vial should be dissolved in sterile water 

for injection or 0.9% sodium chloride as follows:

Shake the vial well to assure complete dissolution before measuring and transferring each individual dose.