Valacyclovir: Package Insert and Label Information (Page 3 of 4)

12.4 Microbiology

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.
Antiviral Activities: 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: 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.

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 valacyclovir hydrochloride 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)].
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.
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.Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

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 (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 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 hydrochloride 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 hydrochloride 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, 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. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
In a third study, patients were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 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 studies were conducted, one in immunocompetent adults and one in HIV-infected adults.
A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months

Outcome 6 Months 12 Months
Valacyclovir Hydrochloride1 gramonce daily(n = 269) Oral acyclovir400 mgtwice daily(n = 267) Placebo(n = 134) Valacyclovir Hydrochloride1 gramonce daily(n = 269) Oral acyclovir400 mgtwice daily(n = 267) Placebo(n = 134)
Recurrence free 55% 54% 7% 34% 34% 4%
Recurrences 35% 36% 83% 46% 46% 85%
Unknowna 10% 10% 10% 19% 19% 10%

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 valacyclovir hydrochloride 500 mg once daily.
In a second study, 293 HIV-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 hydrochloride 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 prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received valacyclovir hydrochloride, the prestudy median CD4+ cell count was 336 cells/mm3 ; 11% had <100 cells/mm3 , 16% had 100 to 199 cells/mm3 , 42% had 200 to 499 cells/mm3 , and 31% had ≥500 cells/mm3. Outcomes for the overall study population are shown in Table 6.Table 6. Recurrence Rates in HIV-Infected Adults at 6 Months

Outcome Valacyclovir Hydrochloride500 mg twice daily(n = 194) Placebo(n = 99)
Recurrence free 65% 26%
Recurrences 17% 57%
Unknowna 18% 17%

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 study 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 study period. Source partners were randomized to treatment with either valacyclovir hydrochloride 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

Endpoint Valacyclovir Hydrochloride 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%)

a Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition)with valacyclovir hydrochloride versus placebo. Individual results may vary based on consistency of safer sex practices.

14.3 Herpes Zoster


Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir hydrochloride compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir hydrochloride or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir hydrochloride and placebo. In patients greater than 50 years of age, 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 valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively.

14.4 Chickenpox


The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age 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 patients.
The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age 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 patients 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 patients across all age-groups (1 to <12 years of age) 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 patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, 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 2 to <18 years of age.
Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children <2 years of age 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)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50436-0704

NDC: 50436-0704-1 30 TABLET, FILM COATED in a BOTTLE

NDC: 50436-0704-3 90 TABLET, FILM COATED in a BOTTLE

NDC: 50436-0704-4 12 TABLET, FILM COATED in a BOTTLE

NDC: 50436-0704-5 15 TABLET, FILM COATED in a BOTTLE

NDC: 50436-0704-6 24 TABLET, FILM COATED in a BOTTLE

Product: 50436-7050

NDC: 50436-7050-1 30 TABLET, FILM COATED in a BOTTLE

NDC: 50436-7050-3 90 TABLET, FILM COATED in a BOTTLE

NDC: 50436-7050-4 12 TABLET, FILM COATED in a BOTTLE

NDC: 50436-7050-5 15 TABLET, FILM COATED in a BOTTLE

NDC: 50436-7050-6 24 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Importance of Adequate Hydration

Patients should be advised to maintain adequate hydration.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.