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Mechanism Of Action
Valacyclovir is an antiviral drug [see Microbiology].
The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years.
Pharmacokinetics In Adults
Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
The absolute bioavailability of acyclovir after administration of VALTREX is 54.5% ± 9.1% as determined following a 1-gram oral dose of VALTREX and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of VALTREX is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
Acyclovir pharmacokinetic parameter estimates following administration of VALTREX to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of VALTREX from doses between 250 mg to 1 gram.
There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.
Table 3: Mean (±SD) Plasma Acyclovir
Pharmacokinetic Parameters Following Administration of VALTREX to Healthy Adult
(N = 8)
(N = 24, 8 per treatment arm)
|Cmax (±SD) (mcg/mL)||AUC (±SD) (h•mcg/mL)||Cmax (±SD) (mcg/mL)||AUC (±SD) (h•mcg/mL)|
|100 mg||0.83 (±0.14)||2.28 (±0.40)||ND||ND|
|250 mg||2.15 (±0.50)||5.76 (±0.60)||2.11 (±0.33)||5.66 (±1.09)|
|500 mg||3.28 (±0.83)||11.59 (±1.79)||3.69 (±0.87)||9.88 (±2.01)|
|750 mg||4.17 (±1.14)||14.11 (±3.54)||ND||ND|
|1,000 mg||5.65 (±2.37)||19.52 (±6.04)||4.96 (±0.64)||15.70 (±2.27)|
|a Administered 4 times daily for 11 days.
ND = not done.
Distribution: The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
Metabolism: Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of VALTREX, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.
Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1-gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of VALTREX to 12 healthy subjects was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of VALTREX in subjects with normal renal function.
Following administration of VALTREX to subjects with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one-third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m² compared with 679.16 ± 162.76 mL/min/1.73 m² in healthy subjects.
Hepatic Impairment: Administration of VALTREX to subjects with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
HIV-1 Disease: In 9 subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm³ who received VALTREX at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy subjects.
Geriatrics: After single-dose administration of 1 gram of VALTREX 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 VALTREX 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, Use In Specific Populations].
Pediatrics: 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, Use in Specific Populations]. 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 VALTREX to Adults
|Parameter||Pediatric Subjects (20 mg/kg Oral Suspension)||Adults 1-gram Solid Dose of VALTREXa
(N = 15)
|1 - < 2 yr
(N = 6)
|2 - < 6 yr
(N = 12)
|6- < 12 yr
(N = 8)
|AUC (mcg•h/mL) Cmax (mcg/mL)||14.4 (±6.26)||10.1 (±3.35)||13.1 (±3.43)||17.2 (±3.10)|
|4.03 (±1.37)||3.75 (±1.14)||4.71 (±1.20)||4.72 (±1.37)|
|a Historical estimates using pediatric pharmacokinetic sampling schedule.|
When VALTREX is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when VALTREX is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
Antacids: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
Cimetidine: Acyclovir Cmax and AUC following a single dose of VALTREX (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 VALTREX (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.
Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
Probenecid: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.
Mechanism Of Action
Valacyclovir is a nucleoside 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.
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 biochemical assays, acyclovir triphosphate inhibits replication of 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.
The quantitative relationship between the cell culture susceptibility of herpesviruses 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 μM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 μM (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 μM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 of 6 μM (1.35 mcg/mL).
Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised 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 also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
Cold Sores (Herpes Labialis)
Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores. Subjects self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of subjects initiated treatment within 2 hours of onset of symptoms. Subjects were randomized to VALTREX 2 grams twice daily on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2-day regimen did not offer additional benefit over the 1-day regimen.
No significant difference was observed between subjects receiving VALTREX or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
Genital Herpes Infections
Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of VALTREX 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, and the median time to cessation of viral shedding was 3 days.
Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Subjects self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
In 1 trial, subjects were randomized to receive 5 days of treatment with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in subjects with at least 1 positive culture (42% of the overall trial population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
In a third trial, subjects were randomized to receive VALTREX 500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
Two clinical trials were conducted, one in immunocompetent adults and one in HIV-1-infected adults.
A double-blind, 12-month, placebo- and active-controlled trial enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall trial population are shown in Table 5.
Table 5: Recurrence Rates in Immunocompetent Adults at
6 and 12 Months
|Outcome||6 Months||12 Months|
|VALTREX 1 gram Once Daily
(n = 269)
|Oral Acyclovir 400 mg Twice Daily
(n = 267)
|VALTREX 1 gram Once Daily
(n = 269)
|Oral Acyclovir 400 mg Twice Daily
(n = 267)
(n = 134)
|a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.|
Subjects with 9 or fewer recurrences per year showed comparable results with VALTREX 500 mg once daily. In a second trial, 293 HIV-1-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either VALTREX 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median pretrial HIV-1 RNA was 2.6 log10 copies/mL. Among subjects who received VALTREX, the pretrial median CD4+ cell count was 336 cells/mm³; 11% had less than 100 cells/mm³, 16% had 100 to 199 cells/mm³, 42% had 200 to 499 cells/mm³, and 31% had greater than or equal to 500 cells/mm³. Outcomes for the overall trial population are shown in Table 6.
Table 6: Recurrence Rates in HIV-1-Infected Adults at
|Outcome||VALTREX 500 mg Twice Daily
(n = 194)
(n = 99)
|a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.|
Reduction Of Transmission Of Genital Herpes
A double-blind, placebo-controlled trial to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The credit partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the trial period. Source partners were randomized to treatment with either VALTREX 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.
Table 7: Percentage of Susceptible Partners Who
Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints
(n = 743)
(n = 741)
|Symptomatic HSV-2 acquisition||4 (0.5%)||16 (2.2%)|
|HSV-2 seroconversion||12 (1.6%)||24 (3.2%)|
|Overall HSV-2 acquisition||14 (1.9%)||27 (3.6%)|
|a Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with VALTREX versus placebo. Individual results may vary based on consistency of safer sex practices.|
Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. VALTREX was compared with placebo in subjects aged less than 50 years, and with oral acyclovir in subjects aged greater than 50 years. All subjects were treated within 72 hours of appearance of zoster rash. In subjects aged less than 50 years, the median time to cessation of new lesion formation was 2 days for those treated with VALTREX compared with 3 days for those treated with placebo. In subjects aged greater than 50 years, the median time to cessation of new lesions was 3 days in subjects treated with either VALTREX or oral acyclovir. In subjects aged less than 50 years, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of VALTREX and placebo. In subjects aged greater than 50 years, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day VALTREX, 14-day VALTREX, and 7-day oral acyclovir, respectively.
The use of VALTREX for treatment of chickenpox in pediatric subjects aged 2 to less than 18 years is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric subjects.
The single-dose pharmacokinetic and multiple-dose safety trial enrolled 27 pediatric subjects aged 1 to less than 12 years with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric subjects following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric subjects across all age-groups (1 to less than 12 years) were lower (Cmax: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric subjects were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric subjects receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this trial and the safety and extrapolated efficacy data from the acyclovir trials, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients aged 2 to less than 18 years. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children aged less than 2 years have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children aged less than 2 years with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days' duration are not available [see Use In Specific Populations].
Last reviewed on RxList: 3/22/2016
This monograph has been modified to include the generic and brand name in many instances.
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