CLINICAL STUDIES

14 14.1 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.

14.2 Genital Herpes Infections Initial Episode: 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.

Recurrent Episodes: 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.

Suppressive Therapy: 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 a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

Outcome 6 Months 12 Months VALTREX 1 gram Once Daily (n = 269) Oral Acyclovir 400 mg Twice Daily (n = 267) Placebo (n = 134) VALTREX 1 gram Once Daily (n = 269) Oral Acyclovir 400 mg Twice Daily (n = 267) Placebo (n = 134) Recurrence free 55% 54% 7% 34% 34% 4% Recurrences 35% 36% 83% 46% 46% 85% Unknown a 10% 10% 10% 19% 19% 10% 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 log 10 copies/mL.

Among subjects who received VALTREX, the pretrial median CD4+ cell count was 336 cells/mm 3 ; 11% had less than 100 cells/mm 3 , 16% had 100 to 199 cells/mm 3 , 42% had 200 to 499 cells/mm 3 , and 31% had greater than or equal to 500 cells/mm 3 .

Outcomes for the overall trial population are shown in Table 6.

Table 6.

Recurrence Rates in HIV─1-Infected Adults at 6 Months a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

Outcome VALTREX 500 mg Twice Daily (n = 194) Placebo (n = 99) Recurrence free 65% 26% Recurrences 17% 57% Unknown a 18% 17% 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 source 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 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.

Endpoint VALTREX a (n = 743) Placebo (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%) 14.3 Herpes Zoster 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.

14.4 Chickenpox 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 (C max : ↓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 (8.4)] .