1.1 Adult Patients

1.2 Pediatric Patients

1.3 Limitations of Use

The efficacy and safety of valacyclovir have not been established in:

• Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count ≥ 100 cells/mm 3.
• Patients < 12 years of age with cold sores (herpes labialis).
• Patients < 2 years of age or ≥ 18 years of age with chickenpox.
• Patients < 18 years of age with genital herpes.
• Patients < 18 years of age with herpes zoster.
• Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

2.1 Adult Dosing Recommendations

2.2 Pediatric Dosing Recommendations

2.3 Extemporaneous Preparation of Oral Suspension

2.4 Patients with Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)] . Data are not available for the use of valacyclovir in pediatric patients with a creatinine clearance < 50 mL/min/1.73 m 2.

5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)

TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir tablets at doses of 8 grams per day. Treatment with valacyclovir tablets should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.

5.2 Acute Renal Failure

Cases of acute renal failure have been reported in:

• Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir tablets to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4), Use in Specific Populations (8.5)] .
• Patients with underlying renal disease who received higher than recommended doses of valacyclovir tablets for their level of renal function. Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].
• Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir tablets to patients receiving potentially nephrotoxic drugs.
• Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.

In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4), Adverse Reactions (6.3)] .

5.3 Central Nervous System Effects

Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir tablets for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir tablets should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)] .

6.1 Clinical Trials Experience in Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Clinical Trials Experience in Pediatric Patients

The safety profile of valacyclovir tablets has been studied in 177 pediatric patients 1 month to < 18 years of age. Sixty-five of these pediatric patients, 12 to < 18 years of age, received oral caplets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to < 12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.

6.3 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir tablets. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir tablets.

General: Facial edema, hypertension, tachycardia.

Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)] .

CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), (8.6)].

Eye:  Visual abnormalities.

Gastrointestinal:  Diarrhea.

Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.

Renal:  Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), (8.6)] .

Hematologic:  Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1)] .

Skin: Erythema multiforme, rashes including photosensitivity, alopecia.

8.1 Pregnancy

8.3 Nursing Mothers

Following oral administration of a 500 mg dose of valacyclovir tablets to 5 nursing mothers, peak acyclovir concentrations (C max) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of valacyclovir twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when valacyclovir tablets are administered to a nursing woman.

8.4 Pediatric Use

Valacyclovir is indicated for treatment of cold sores in pediatric patients ≥ 12 years of age and for treatment of chickenpox in pediatric patients 2 to < 18 years of age [see Indications and Usage (1.2), Dosage and Administration (2.2)].

The use of valacyclovir tablets for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥ 12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)] .

The use of valacyclovir 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 efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

The efficacy and safety of valacyclovir have not been established in pediatric patients:

• < 12 years of age with cold sores
• < 18 years of age with genital herpes
• < 18 years of age with herpes zoster
• < 2 years of age with chickenpox
• for suppressive therapy following neonatal HSV infection.

The pharmacokinetic profile and safety of valacyclovir oral suspension in children < 12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.

Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to < 12 years of age with clinically suspected varicella-zoster virus (VZV) infection [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)] .

Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to < 6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children 3 months to < 6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to < 3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (C max: ↑ 30%, AUC: ↑ 60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir.

Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to < 12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 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 recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to < 12 years of age) were lower (C max: ↓ 20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑ 16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to < 12 years of age with recurrent genital herpes.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of valacyclovir tablets, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.3)] .

8.6 Renal Impairment

Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

12.1 Mechanism of Action

Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir tablets have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to < 12 years of age.

12.4 Microbiology

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 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)].

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.

14.1 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 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

14.3 Herpes Zoster

Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir tablets were 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 tablets 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 tablets 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 tablets 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 tablets, 14-day valacyclovir tablets, and 7-day oral acyclovir, respectively.

14.4 Chickenpox

The use of valacyclovir 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 (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 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)] .

17.1 Importance of Adequate Hydration

Patients should be advised to maintain adequate hydration.

17.2 Cold Sores (Herpes Labialis)

Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir tablets are not a cure for cold sores.

17.3 Genital Herpes

Patients should be informed that valacyclovir tablets are not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir tablets. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.

Valacyclovir tablets have not been shown to reduce transmission of sexually transmitted infections other than HSV-2.

If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.

There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients.

17.4 Herpes Zoster

There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

17.5 Chickenpox

Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.