Valacyclovir Hydrochloride (Page 10 of 13)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram of valacyclovir tablets given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology (12.3)].

Carcinogenesis

Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.

Mutagenesis

Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.

In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.

Valacyclovir was mutagenic in a mouse micronucleus assay.

Impairment of Fertility

Valacyclovir did not impair fertility or reproduction in male or female rats at acyclovir exposures (AUC) 6 times higher than in humans given the MRHD. Testicular atrophy occurred in male rats (orally dosed for 97 days at 18 times the MRHD) and was reversible.

14 CLINICAL STUDIES

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 valacyclovir tablets 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir tablets 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 valacyclovir tablets 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 valacyclovir tablets 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 valacyclovir tablets 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir tablets 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 valacyclovir tablets 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir tablets 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 valacyclovir tablets 500 mg twice daily for 5 days (n = 398) or valacyclovir tablets 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 8.

Table 8. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months

* Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.
Outcome	6 Months			12 Months
	Valacyclovir Tablets 1 gram Once Daily (n = 269)	Oral Acyclovir 400 mg Twice Daily (n = 267)	Placebo (n = 134)	Valacyclovir Tablets 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 *	10%	10%	10%	19%	19%	10%

Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir tablets 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 valacyclovir tablets 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 valacyclovir tablets, 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 9.

Table 9. Recurrence Rates in HIV-1–Infected Adults at 6 Months

* Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.
Outcome	Valacyclovir Tablets 500 mg Twice Daily (n = 194)	Placebo (n = 99)
Recurrence free	65%	26%
Recurrences	17%	57%
Unknown *	18%	17%