Valacyclovir: prescribing information – dosing, contraindications, interactions, side effects

1.1 Adult Patients

Cold Sores (Herpes Labialis)

VALTREX is indicated for treatment of cold sores (herpes labialis). The efficacy of VALTREX 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: VALTREX is indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with VALTREX when initiated more than 72 hours after the onset of signs and symptoms has not been established.

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

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

Reduction of Transmission: VALTREX is indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of VALTREX for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of VALTREX 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

VALTREX is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of VALTREX when initiated more than 72 hours after the onset of rash and the efficacy and safety of VALTREX for treatment of disseminated herpes zoster have not been established.

1.2 Pediatric Patients

Cold Sores (Herpes Labialis)

VALTREX is indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years. The efficacy of VALTREX initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.

Chickenpox

VALTREX is indicated for the treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years. Based on efficacy data from clinical trials with oral acyclovir, treatment with VALTREX should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4)].

1.3 Limitations of Use

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

• •Immunocompromised patients other than for the suppression of genital herpes in HIV‑1−infected patients with a CD4+ cell count greater than or equal to 100 cells/mm³.
• •Patients aged less than 12 years with cold sores (herpes labialis).
• •Patients aged less than 2 years or greater than or equal to 18 years with chickenpox.
• •Patients aged less than 18 years with genital herpes.
• •Patients aged less than 18 years with herpes zoster.
• •Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

• •VALTREX may be given without regard to meals.
• •Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg VALTREX tablets for use in pediatric patients for whom a solid dosage form is not appropriate [see Dosage and Administration (2.3)].

2.1 Adult Dosing Recommendations

Cold Sores (Herpes Labialis)

The recommended dosage of VALTREX 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 VALTREX 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 VALTREX 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 VALTREX 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‑1−infected patients with a CD4+ cell count greater than or equal to 100 cells/mm³, the recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

Reduction of Transmission: The recommended dosage of VALTREX 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 VALTREX 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 VALTREX for the treatment of cold sores in pediatric patients aged greater than or equal to 12 years 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).

Chickenpox

The recommended dosage of VALTREX for treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

2.3 Extemporaneous Preparation of Oral Suspension

Ingredients and Preparation per USP‑NF

VALTREX tablets 500 mg, cherry flavor, and Suspension Structured Vehicle USP-NF (SSV). Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of 100 mL.

Instructions for Preparing Suspension at Time of Dispensing

• •Prepare SSV according to the USP-NF.
• •Using a pestle and mortar, grind the required number of VALTREX 500-mg tablets until a fine powder is produced (5 VALTREX tablets for 25-mg/mL suspension; 10 VALTREX tablets for 50-mg/mL suspension).
• •Gradually add approximately 5-mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted.
• •Continue to add approximately 5-mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50-mg/mL suspensions.
• •Transfer the mixture to a suitable 100-mL measuring flask.
• •Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV. Once dissolved, add to the measuring flask.
• •Rinse the mortar at least 3 times with approximately 5-mL aliquots of SSV, transferring the rinsing to the measuring flask between additions.
• •Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix.
• •Transfer the suspension to an amber glass medicine bottle with a child-resistant closure.
• •The prepared suspension should be labeled with the following information “Shake well before using. Store suspension between 2°C to 8°C (36°F to 46°F) in a refrigerator. Discard after 28 days.”

*The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.

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 VALTREX in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m².

Table 1. VALTREX Dosage Recommendations for Adults with Renal Impairment
Indications | Normal Dosage Regimen (Creatinine Clearance ≥50 mL/min) | Creatinine Clearance (mL/min)
30-49 | 10-29 | <10
Cold sores (Herpes Labialis) Do not exceed 1 day of treatment. | Two 2-gram doses taken 12 hours apart | Two 1-gram doses taken 12 hours apart | Two 500-mg doses taken 12 hours apart | 500-mg single dose
Genital herpes: Initial episode | 1 gram every 12 hours | no reduction | 1 gram every 24 hours | 500 mg every 24 hours
Genital herpes: Recurrent episode | 500 mg every 12 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours
Genital herpes: Suppressive therapy | | | |
Immunocompetent patients | 1 gram every 24 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours
Alternate dose for immunocompetent patients with less than or equal to 9 recurrences/year | 500 mg every 24 hours | no reduction | 500 mg every 48 hours | 500 mg every 48 hours
HIV‑1−infected patients | 500 mg every 12 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours
Herpes zoster | 1 gram every 8 hours | 1 gram every 12 hours | 1 gram every 24 hours | 500 mg every 24 hours

Hemodialysis

Patients requiring hemodialysis should receive the recommended dose of VALTREX after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of VALTREX 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 VALTREX 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 VALTREX should not be required following CAPD or CAVHD.

Tablets:

• •500-mg: Each blue, film‑coated, capsule‑shaped tablet printed with “VALTREX 500 mg” contains 556.2 mg of valacyclovir hydrochloride equivalent to 500 mg of the free base.
• •1-gram: Each blue, film‑coated, capsule‑shaped tablet, with a partial scorebar on both sides, printed with “VALTREX 1 gram” contains 1.112 grams of valacyclovir hydrochloride equivalent to 1 gram of the free base.

VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction [e.g., anaphylaxis, severe cutaneous adverse reactions (SCARs)] to valacyclovir, acyclovir, or any component of the formulation [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.3 )] .

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• •Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)].
• •Acute Renal Failure [see Warnings and Precautions (5.2)].
• •Central Nervous System Effects [see Warnings and Precautions (5.3)].
• •Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.4)].

The most common adverse reactions reported in at least 1 indication by greater than 10% of adult subjects treated with VALTREX and observed more frequently with VALTREX compared with placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric subjects aged less than 18 years was headache.

6.1 Clinical Trials Experience in Adult Subjects

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 trials for the treatment of cold sores, the adverse reactions reported by subjects receiving VALTREX 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 (greater than 2 x ULN) were 1.8% for subjects receiving VALTREX 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 trial for the treatment of initial episodes of genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving VALTREX 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 trials for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving VALTREX 500 mg twice daily for 3 days (n = 402), VALTREX 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 trial for the suppression of recurrent genital herpes infections, the adverse reactions reported by subjects receiving VALTREX 1 gram once daily (n = 269), VALTREX 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-1–Infected Subjects: In HIV-1–infected subjects, frequently reported adverse reactions for VALTREX (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 trial for the reduction of transmission of genital herpes, the adverse reactions reported by subjects receiving VALTREX 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 trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving VALTREX 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.

Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations
a Data were not collected prospectively. LLN = Lower limit of normal. ULN = Upper limit of normal.
Laboratory Abnormality | Herpes Zoster | Genital Herpes Treatment | Genital Herpes Suppression
VALTREX 1 gram 3 Times Daily (n = 967) | Placebo (n = 195) | VALTREX 1 gram Twice Daily (n = 1,194) | VALTREX 500 mg Twice Daily (n = 1,159) | Placebo (n = 439) | VALTREX 1 gram Once Daily (n = 269) | VALTREX 500 mg Once Daily (n = 266) | Placebo (n = 134)
Hemoglobin (<0.8 x LLN) | 0.8% | 0% | 0.3% | 0.2% | 0% | 0% | 0.8% | 0.8%
White blood cells (<0.75 x LLN) | 1.3% | 0.6% | 0.7% | 0.6% | 0.2% | 0.7% | 0.8% | 1.5%
Platelet count (<100,000/mm³) | 1.0% | 1.2% | 0.3% | 0.1% | 0.7% | 0.4% | 1.1% | 1.5%
AST (SGOT) (>2 x ULN) | 1.0% | 0% | 1.0% | a | 0.5% | 4.1% | 3.8% | 3.0%
Serum creatinine (>1.5 x ULN) | 0.2% | 0% | 0.7% | 0% | 0% | 0% | 0% | 0%

6.2 Clinical Trials Experience in Pediatric Subjects

The safety profile of VALTREX has been studied in 177 pediatric subjects aged 1 month to less than 18 years. Sixty-five of these pediatric subjects, aged 12 to less than 18 years, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric subjects, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety trials and received valacyclovir oral suspension. Fifty-one of these 112 pediatric subjects 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.

Pediatric Subjects Aged 12 to Less than 18 Years (Cold Sores)

In clinical trials for the treatment of cold sores, the adverse reactions reported by adolescent subjects receiving VALTREX 2 grams twice daily for 1 day, or VALTREX 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%).

Pediatric Subjects Aged 1 Month to Less than 12 Years

Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials in children aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.

6.3 Postmarketing Experience

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

General

Facial edema, hypertension, tachycardia.

Allergic

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

Central Nervous System (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 and Subcutaneous Tissue Disorders

Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), Stevens‑Johnson syndrome (SJS), erythema multiforme (EM), rashes including photosensitivity, alopecia [see Contraindications (4), Warnings and Precautions (5.4)].

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-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of VALTREX at doses of 8 grams per day. Treatment with VALTREX 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 VALTREX 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 VALTREX for their level of renal function. Dosage reduction is recommended when administering VALTREX 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 VALTREX 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 VALTREX for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. VALTREX should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].

5.4 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens‑Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported during postmarketing experience with valacyclovir [see Contraindications ( 4 ) and Adverse Reactions ( 6.3 )] . Discontinue VALTREX immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. VALTREX is contraindicated in patients who have developed SCARs with the use of valacyclovir or acyclovir, or any component of the formulation [see Contraindications ( 4 ), Adverse Reactions ( 6.3 )] .

No clinically significant drug-drug or drug-food interactions with VALTREX are known [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified a drug associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes (see Data). There are risks to the fetus associated with untreated herpes simplex during pregnancy (see Clinical Considerations).

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with valacyclovir when administered to pregnant rats and rabbits at system exposures (AUC) 4 (rats) and 7 (rabbits) times the human exposure at the maximum recommended human dose (MRHD) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: The risk of neonatal HSV infection varies from 30% to 50% for genital HSV acquired in late pregnancy (third trimester), whereas with HSV acquisition in early pregnancy, the risk of neonatal infection is about 1%. A primary herpes occurrence during the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and, in rare cases, skin lesions. In very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth. Co-infection with HSV increases the risk of perinatal HIV transmission in women who had a clinical diagnosis of genital herpes during pregnancy.

Data

Human Data: Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, based on published literature, have not identified a drug-associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes.

The Acyclovir and the Valacyclovir Pregnancy Registries, both population-based international prospective studies, collected pregnancy data through April 1999. The Acyclovir Registry documented outcomes of 1,246 infants and fetuses exposed to acyclovir during pregnancy (756 with earliest exposure during the first trimester, 197 during the second trimester, 291 during the third trimester, and 2 unknown). The occurrence of major birth defects during first-trimester exposure to acyclovir was 3.2% (95% CI: 2.0% to 5.0%) and during any trimester of exposure was 2.6% (95% CI: 1.8% to 3.8%). The Valacyclovir Pregnancy Registry documented outcomes of 111 infants and fetuses exposed to valacyclovir during pregnancy (28 with earliest exposure in the first trimester, 31 during the second trimester, and 52 during the third trimester).The occurrence of major birth defects during first-trimester exposure to valacyclovir was 4.5% (95% CI: 0.24% to 24.9%) and during any trimester of exposure was 3.9% (95% CI: 1.3% to 10.7%).

Available studies have methodological limitations including insufficient sample size to support conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects.

Animal Data: Valacyclovir was administered orally to pregnant rats and rabbits (up to 400 mg/kg/day) during organogenesis (Gestation Days 6 through 15, and 6 through 18, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (AUC) of up to approximately 4 (rats) and 7 (rabbits) times the exposure in humans at the MRHD. Early embryo death, fetal growth retardation (weight and length), and variations in fetal skeletal development (primarily extra ribs and delayed ossification of sternebrae) were observed in rats and associated with maternal toxicity (200 mg/kg/day; approximately 6 times higher than human exposure at the MRHD).

In a pre/postnatal development study, valacyclovir was administered orally to pregnant rats (up to 200 mg/kg/day from Gestation Day 15 to Post-Partum Day 20) from late gestation through lactation. No significant adverse effects were observed in offspring exposed daily from before birth through lactation at maternal exposures (AUC) of approximately 6 times higher than human exposures at the MRHD.

8.2 Lactation

Risk Summary

Although there is no information on the presence of valacyclovir in human milk, its metabolite, acyclovir, is present in human milk following oral administration of valacyclovir. Based on published data, a 500-mg maternal dose of VALTREX twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day (see Data). There is no data on the effects of valacyclovir or acyclovir on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VALTREX and any potential adverse effects on the breastfed child from VALTREX or from the underlying maternal condition.

Data

Following oral administration of a 500-mg dose of VALTREX to 5 lactating women, 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 dose of VALTREX twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day. Unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine.

8.4 Pediatric Use

VALTREX is indicated for treatment of cold sores in pediatric patients aged greater than or equal to 12 years and for treatment of chickenpox in pediatric patients aged 2 to less than 18 years [see Indications and Usage (1.2), Dosage and Administration (2.2)].

The use of VALTREX for treatment of cold sores is based on 2 double‑blind, placebo‑controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores [see Clinical Studies (14.1)].

The use of VALTREX for treatment of chickenpox in pediatric patients 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 efficacy and safety data from 3 randomized, double‑blind, placebo‑controlled trials evaluating oral acyclovir in pediatric subjects 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:

• •aged less than 12 years with cold sores
• •aged less than 18 years with genital herpes
• •aged less than 18 years with herpes zoster
• •aged less than 2 years with chickenpox
• •for suppressive therapy following neonatal HSV infection.

The pharmacokinetic profile and safety of valacyclovir oral suspension in children aged less than 12 years were studied in 3 open‑label trials. No efficacy evaluations were conducted in any of the 3 trials.

Trial 1 was a single‑dose pharmacokinetic, multiple‑dose safety trial in 27 pediatric subjects aged 1 to less than 12 years 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)].

Trial 2 was a single‑dose pharmacokinetic and safety trial in pediatric subjects aged 1 month to less than 6 years 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 aged 3 months to less than 6 years, this dose provided comparable systemic acyclovir exposures to that from a 1‑gram dose of valacyclovir in adults (historical data). In infants aged 1 month to less than 3 months, 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. 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.

Trial 3 was a single‑dose pharmacokinetic, multiple‑dose safety trial in 28 pediatric subjects aged 1 to less than 12 years with clinically suspected HSV infection. None of the subjects enrolled in this trial 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 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 recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric subjects across all age‑groups (1 to less than 12 years) were lower (Cmax: ↓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 aged 1 to less than 12 years with recurrent genital herpes.

8.5 Geriatric Use

Of the total number of subjects in clinical trials of VALTREX, 906 were 65 and over, and 352 were 75 and over. In a clinical trial of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in subjects 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 VALTREX to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5, 8.6)]. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. 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)].

12.1 Mechanism of Action

Valacyclovir is an antiviral drug active against α-herpes viruses [see Microbiology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years.

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

Table 3. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of VALTREX to Healthy Adult Volunteers
a Administered 4 times daily for 11 days. ND = not done.
Dose | Single‑Dose Administration (N = 8) | Multiple‑Dose Administrationa (N = 24, 8 per treatment arm)
Cmax (±SD) (mcg/mL) | AUC (±SD) (h●mcg/mL) | Cmax (±SD) (mcg/mL) | AUC (±SD) (h●mcg/mL)
100 mg | 0.83 (±0.14) | 2.28 (±0.40) | ND | ND
250 mg | 2.15 (±0.50) | 5.76 (±0.60) | 2.11 (±0.33) | 5.66 (±1.09)
500 mg | 3.28 (±0.83) | 11.59 (±1.79) | 3.69 (±0.87) | 9.88 (±2.01)
750 mg | 4.17 (±1.14) | 14.11 (±3.54) | ND | ND
1,000 mg | 5.65 (±2.37) | 19.52 (±6.04) | 4.96 (±0.64) | 15.70 (±2.27)

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%.