Valacyclovir Hydrochloride (Page 8 of 13)

Geriatric Patients

After single-dose administration of 1 gram of valacyclovir tablets in healthy geriatric subjects, the half-life of acyclovir was 3.11 ± 0.51 hours compared with 2.91 ± 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir tablets in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].

Pediatric Patients

Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric subjects (aged 1 month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following a 20-mg/kg dose are provided in Table 4.

Table 4. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Subjects vs. 1-Gram Single Dose of Valacyclovir Tablets to Adults
Historical estimates using pediatric pharmacokinetic sampling schedule.


Pediatric Subjects

(20 mg/kg Oral Suspension)


1-gram Solid Dose of Valacyclovir Tablets *

(N = 15)

1 — < 2 year

(N = 6)

2 — < 6 year

(N = 12)

6 — < 12 year

(N = 8)

AUC (mcg•hr/mL)

14.4 (± 6.26)

10.1 (± 3.35)

13.1 (± 3.43)

17.2 (± 3.10)

Cmax (mcg/mL)

4.03 (± 1.37)

3.75 (± 1.14)

4.71 (± 1.20)

4.72 (± 1.37)

Drug Interaction Studies

When valacyclovir tablets are coadministered with antacids, cimetidine and/or probenecid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir tablets are coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.


The pharmacokinetics of acyclovir after a single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).


Acyclovir Cmax and AUC following a single dose of valacyclovir tablets (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

Cimetidine Plus Probenecid

Acyclovir Cmax and AUC following a single dose of valacyclovir tablets (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.


The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir tablets 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir tablets (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).


Acyclovir Cmax and AUC following a single dose of valacyclovir tablets (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).

Thiazide Diuretics

The pharmacokinetics of acyclovir after a single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

12.4 Microbiology

Mechanism of Action

Valacyclovir is a deoxynucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.

Acyclovir is a synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK; pUL23) of HSV or VZV 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 biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation 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 with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activity

The quantitative relationship between the cell culture 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 (EC50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 microM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 microM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 microM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 value of 6 microM (1.35 mcg/mL).


In Cell Culture

Acyclovir-resistant HSV-1, HSV-2, and VZV strains were isolated in cell culture. Acyclovir-resistant HSV and VZV resulted from mutations in the viral thymidine kinase (TK, pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture, acyclovir resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 5).

Table 5. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions in Cell Culture






P5A, H7Q, L50V, G56V, G59R/V/W/A, G61A/V, K62I/N, T63A, E83K, P84L/S, R89W, D116N, P131S, P155R, F161I/C, R163H/P, A167V, P173L, R176Q/W, Q185R, A189L/V, G200S, G206R, R216S, R220H, L227F, Y239S, T245M, Q261stop, R281stop, T287M, M322K, C336Y, V348A



L69P, C172R, A175V, T288M



D368A, Y557S, E597D, V621S, L702H, A719V, S742N, N815S, V817M, Y818C, G841C/S



No substitutions detected

All resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2023. All Rights Reserved.