1.1       Adult Patients

            Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir hydrochloride tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.

            Genital Herpes: Initial Episode: Valacyclovir hydrochloride tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established.

            Recurrent Episodes: Valacyclovir hydrochloride tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir hydrochloride tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established.

            Suppressive Therapy: Valacyclovir hydrochloride tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of valacyclovir hydrochloride tablets for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established.

            Reduction of Transmission: Valacyclovir hydrochloride tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir hydrochloride tablets for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of valacyclovir hydrochloride tablets for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines).

            Herpes Zoster: Valacyclovir hydrochloride tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir hydrochloride tablets for treatment of disseminated herpes zoster have not been established.

1.2       Pediatric Patients

      Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients ≥12 years of age. The efficacy of valacyclovir hydrochloride tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.

      Labeling describing use of valacyclovir HCL in pediatric patients with chickenpox (ages 2 to ≤ 18 years) is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that pediatric use is not approved for this valacyclovir HCL tablet product.

1.3       Limitations of Use

The efficacy and safety of valacyclovir hydrochloride tablets 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/mm3.
  
• Patients <12 years of age with cold sores (herpes labialis).
  
• 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.

      Labeling describing use of valacyclovir HCL in pediatric patients with chickenpox (ages of 2 to ≤ 18 years) is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that pediatric use is not approved for this valacyclovir HCL tablet product.

2.1       Adult Dosing Recommendations

      Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

      Genital Herpes: Initial Episode: The recommended dosage of valacyclovir hydrochloride tablets for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

      Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride tablets for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.

      Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.

      In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

      Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride tablets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.

      Herpes Zoster: The recommended dosage of valacyclovir hydrochloride tablets for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.

2.2       Pediatric Dosing Recommendations

      Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for the treatment of cold sores in pediatric patients ≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

      Labeling describing additional dosing of valacyclovir HCL for pediatric patients with chickenpox is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that additional dosing information is not approved for this valacyclovir HCL tablet product.

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 hydrochloride tablets in pediatric patients with a creatinine clearance <50 mL/min/1.73 m2.

      Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of valacyclovir hydrochloride tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride tablets is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.

      Peritoneal Dialysis: There is no information specific to administration of valacyclovir hydrochloride tablets in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of valacyclovir hydrochloride tablets should not be required following CAPD or CAVHD.

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 hydrochloride tablets at doses of 8 grams per day. Treatment with valacyclovir hydrochloride 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 hydrochloride 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 hydrochloride tablets for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride 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 hydrochloride 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 hydrochloride tablets for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride 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.

      Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving valacyclovir hydrochloride tablets 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving valacyclovir hydrochloride tablets compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.

      Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride tablets 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.

      Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride tablets 500 mg twice daily for 3 days (n = 402), valacyclovir hydrochloride tablets 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.

      Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving valacyclovir hydrochloride tablets 1 gram once daily (n = 269), valacyclovir hydrochloride tablets 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%; 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.

      Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for valacyclovir hydrochloride tablets (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.

      Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving valacyclovir hydrochloride tablets 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).

      Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir hydrochloride tablets 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.

LLN = Lower limit of normal.

ULN = Upper limit of normal.

6.2       Clinical Trials Experience in Pediatric Patients

      Sixty-five pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.

      Pediatric Patients 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride tablets 2 grams twice daily for 1 day, or valacyclovir hydrochloride tablets 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).

      Labeling describing additional clinical trial adverse reactions in pediatric patients (ages of 1 month to ≤ 12 years) is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those adverse reactions is not approved for this valacyclovir HCL tablet product.

6.3       Postmarketing Experience

      In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride 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 hydrochloride 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

      Pregnancy Category B. There are no adequate and well-controlled studies of valacyclovir or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in utero appears similar to the rate for infants in the general population. Valacyclovir hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

      A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.

      Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.

8.3       Nursing Mothers

      Following oral administration of a 500 mg dose of valacyclovir hydrochloride tablets to 5 nursing mothers, peak acyclovir concentrations (Cmax)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 hydrochloride tablets 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 hydrochloride tablets are administered to a nursing woman.

8.4       Pediatric Use

      Valacyclovir hydrochloride tablets are indicated for treatment of cold sores in pediatric patients ≥12 years of age [see Indications and Usage (1.2), Dosage and Administration (2.2)].

      The use of valacyclovir hydrochloride 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 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
  
• for suppressive therapy following neonatal HSV infection.

      In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults.

      Labeling describing pediatric use information in pediatric patients with chickenpox (ages 2 to ≤ 18 years) and additional pharmacokinetic studies in pediatric patients (ages 3 months to < 12 years) treated with valacyclovir HCL is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, that additional pediatric information is not approved for this valacylcovir HCL tablet product.

8.5       Geriatric Use

      Of the total number of subjects in clinical studies of valacyclovir hydrochloride 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 hydrochloride 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 hydrochloride tablets have been investigated in 14 volunteer studies involving 283 adults.

      Labeling describing use of valacyclovir in pediatric patients with chickenpox (ages 1 month to < 12 years) is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, that additional pediatric information is not approved for this valacylcovir HCL tablet product.

      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 valacyclovir hydrochloride tablets is 54.5% ± 9.1% as determined following a 1 gram oral dose of valacyclovir and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir hydrochloride tablets 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 valacyclovir hydrochloride tablets 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 valacyclovir hydrochloride tablets 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.

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 valacyclovir hydrochloride tablets, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers 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 valacyclovir hydrochloride tablets to 12 healthy volunteers 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 studies of valacyclovir hydrochloride tablets in volunteers with normal renal function.

      Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)].

      Following administration of valacyclovir hydrochloride tablets to volunteers 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 dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.

      Hepatic Impairment: Administration of valacyclovir hydrochloride tablets to patients 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 Disease: In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm3 who received valacyclovir hydrochloride tablets 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 volunteers.

      Geriatrics: After single-dose administration of 1 gram of valacyclovir hydrochloride tablets in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir hydrochloride tablets in geriatric volunteers 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 (2.4), Use in Specific Populations (8.5), (8.6)].

            Labeling describing additional pharmacokinetic studies with valacyclovir HCL in pediatric patients (ages of 1 month to < 12 years) is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those pharmacokinetic studies is not approved for this valacylcovir HCL tablet product.

      Drug Interactions: When valacyclovir hydrochloride tablets are 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 valacyclovir hydrochloride tablets are 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 valacyclovir hydrochloride tablets (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 valacyclovir hydrochloride tablets (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 valacyclovir hydrochloride tablets (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 valacyclovir hydrochloride tablets 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride tablets (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

      Probenecid: Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride tablets (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).

      Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride tablets (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

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 herpes viruses 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.

13.1       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 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 hydrochloride tablets 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 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 hydrochloride 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 and 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 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, 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 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 hydrochloride tablets 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 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 hydrochloride tablets 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 tablets 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 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 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.

      Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride tablets 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 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 prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received valacyclovir hydrochloride tablets, 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.

      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 tablets 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.

14.3       Herpes Zoster

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

      Labeling describing clinical studies of valacyclovir HCL in pediatric patients with chickenpox (ages 2 to ≤ 18 years) for the treatment of chickenpox is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those clinical studies is not approved for this valacyclovir HCL tablet product.

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 hydrochloride tablets are not a cure for cold sores.

17.3       Genital Herpes

      Patients should be informed that valacyclovir hydrochloride 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 hydrochloride 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 hydrochloride 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.

      Labeling describing use of valacyclovir HCL in pediatric patients with chickenpox (ages of 2 to ≤ 18 years) for the treatment of chickenpox is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that use is not approved for this valacyclovir HCL tablet product.

17.6       FDA-Approved Patient Labeling

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