Version July 2025
INTRODUCTION —
Valacyclovir is the valyl ester of the antiviral drug acyclovir [1]. Acting as an oral prodrug, valacyclovir is converted in vivo to acyclovir. Acyclovir, a nucleoside analog, is phosphorylated by virally-encoded thymidine kinase and subsequently by cellular enzymes, yielding acyclovir triphosphate, which competitively inhibits viral DNA polymerase. (See "Acyclovir: An overview".)
BASIC PHARMACOKINETICS —
Valacyclovir has three to fivefold greater oral bioavailability (about 55 percent) than acyclovir; it then undergoes rapid and extensive first-pass intestinal and/or hepatic hydrolysis to yield acyclovir and L-valine [2,3]. Food does not affect absorption.
Valacyclovir, at a dose of 250 mg four times daily, generates essentially the same acyclovir AUC (area under the curve, or exposure over 24 hours) as oral acyclovir at a dose 800 mg five times daily [3]. Valacyclovir, at a dose of 1000 mg three times daily, produces a similar acyclovir AUC as intravenous acyclovir at a dose of 5 mg/kg every eight hours [4].
Intravenous acyclovir generates higher peak levels than oral valacyclovir. Although this feature may confer more potent activity, it may also increase the risk of renal toxicity due to precipitation of acyclovir crystals in the renal tubules [3] (see "Crystalline-induced acute kidney injury"). In addition, the safety of valacyclovir at doses higher than those approved by the US Food and Drug Administration, especially in immunocompromised persons, remains controversial. (See 'Toxicity' below.)
The main route of acyclovir elimination is renal, and dose modification is recommended for patients with a creatinine clearance below 30 mL/min/1.73 m2. Dose adjustment is not required in patients with hepatic impairment [3].
MECHANISM OF RESISTANCE —
The mechanisms of resistance to valacyclovir are identical to those described for acyclovir. Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host [5]:
●Reduced or absent thymidine kinase
●Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation
●Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate
(See "Acyclovir: An overview", section on 'Mechanism of resistance'.)
CLINICAL USE —
Valacyclovir can generally be regarded as an acceptable alternative to oral acyclovir when this drug is indicated and features a more convenient dosing schedule. (See 'Basic pharmacokinetics' above.)
The antiviral activity of valacyclovir reflects its in vivo conversion to acyclovir, which is active against viruses such as herpes simplex virus types 1 and 2, varicella-zoster virus, and B virus. It also has activity against Epstein Barr Virus (EBV), although it is not usually used clinically for EBV infections. Cytomegalovirus (CMV), which does not encode thymidine kinase, is resistant at the oral doses of approved by the US Food and Drug Administration [2,3]. (See "Acyclovir: An overview", section on 'Spectrum of activity'.)
More detailed information on the use of valacyclovir for treatment of these conditions is discussed elsewhere. (See "Treatment of herpes zoster" and "Treatment of genital herpes simplex virus infection" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults" and "B virus infection".)
TOXICITY —
When administered at approved doses (up to 1000 mg three times daily, or two 2000 mg doses separated by 12 hours), valacyclovir has been remarkably well tolerated, similar to the experience with acyclovir [1,3]. (See "Treatment of herpes zoster" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)
However, a trial examining the effectiveness of high-dose valacyclovir (2000 mg four times daily) in preventing cytomegalovirus (CMV) disease was halted when interim analysis revealed significantly shorter survival in patients receiving this regimen, with cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome being reported [6]. This complication has also been observed at this high dose in recipients of allogeneic bone marrow or kidney transplants [1].
Much of this phenomenon was attributed to the development of a thrombotic microangiopathy associated with valacyclovir; however, causality has not been established conclusively, since several other medications (fluconazole, ethambutol, clofazimine, trimethoprim-sulfamethoxazole) were also significantly associated with this complication [7]. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
USE IN PREGNANCY —
There does not appear to be an increased risk of birth defects when valacyclovir is administered during the first trimester of pregnancy; however, controlled studies documenting safety are lacking. Prospective epidemiologic registries of acyclovir and valacyclovir in pregnancy, which collected data through 1999, found that the rate of birth defects among 784 infants and fetuses exposed to these agents during the first trimester was not significantly different from that of the population not exposed to these agents [1]. Similar findings were demonstrated in a study of 1804 first-trimester pregnancies in Denmark exposed to acyclovir, valacyclovir, or famciclovir from 1996 to 2008, in which the frequency of major birth defects in exposed infants was not increased compared with those who were not exposed (2.2 versus 2.4 percent, adjusted prevalence odds ratio 0.89; 95% CI 0.65-1.22) [8]. With regards to the individual antiviral agents, a major birth defect was diagnosed in 32 of 1561 infants (2.0 percent) with first-trimester exposure to acyclovir and 7 of 229 infants (3.1 percent) with first-trimester exposure to valacyclovir; famciclovir exposure was uncommon, with 1 of 26 infants (3.8 percent) diagnosed with a birth defect.
Although the relatively small size of available data yield insufficient power to draw definitive conclusions regarding the safety of acyclovir and valacyclovir in pregnancy, there are circumstances in which the potential benefits of acyclovir and valacyclovir in pregnancy outweigh the risks, given the high potential morbidity of perinatally acquired herpes simplex virus infection. However, valacyclovir is typically considered an alternative to acyclovir in pregnancy since there is less experience with the use of this agent. (See "Genital herpes simplex virus infection and pregnancy".)
SUMMARY AND RECOMMENDATIONS
●Pharmacokinetics and spectrum of activity – Valacyclovir is converted in vivo to acyclovir, a nucleoside analog that competitively inhibits viral DNA polymerase. Valacyclovir has three to fivefold greater oral bioavailability (about 55 percent) than acyclovir. (See 'Introduction' above and 'Basic pharmacokinetics' above.)
●Mechanism of resistance – The mechanism of resistance to valacyclovir is identical to that described for acyclovir. Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host: reduced or absent thymidine kinase, altered thymidine kinase activity, and altered viral DNA polymerase with decreased affinity for acyclovir triphosphate. (See 'Mechanism of resistance' above.)
●Clinical use – Valacyclovir is used clinically for treatment of certain viral infections, such as herpes simplex virus types 1 and 2 and varicella-zoster virus. Valacyclovir can generally be regarded as an acceptable alternative to oral acyclovir when this drug is indicated and offers a more convenient dosing schedule. (See 'Clinical use' above.)
●Toxicity – When administered at approved doses (up to 1000 mg three times daily, or two 2000 mg doses separated by 12 hours), valacyclovir is well tolerated. (See 'Toxicity' above.)
●Use in pregnancy – There does not appear to be an increased risk of birth defects when valacyclovir is administered during the first trimester of pregnancy; however, controlled studies documenting safety are lacking. (See 'Use in pregnancy' above.)
