VALACYCLOVIR tablet, film coated

Valacyclovir by

Drug Labeling and Warnings

Valacyclovir by is a Prescription medication manufactured, distributed, or labeled by McKesson Corporation dba SKY Packaging, Legacy Pharmaceutical Packaging, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.1 Adult patients

    Cold Sores (Herpes Labialis)
    Valacyclovir tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir 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 tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent
    adults. The efficacy of treatment with valacyclovir tablets when initiated more than 72 hours after the onset of signs and
    symptoms has not been established.


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


    Suppressive Therapy: Valacyclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital
    herpes in immunocompetent and in HIV-1–infected adults. The efficacy and safety of valacyclovir tablets 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: Valacyclovir tablets are indicated for the reduction of transmission of genital herpes in
    immunocompetent adults. The efficacy of valacyclovir tablets for the reduction of transmission of genital herpes beyond 8
    months in discordant couples has not been established. The efficacy of valacyclovir 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 tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of
    valacyclovir tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir
    tablets for treatment of disseminated herpes zoster have not been established.

    1.2 Pediatric Patients

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


    Chickenpox
    Valacyclovir tablets are 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 valacyclovir tablets 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 valacyclovir tablets 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.

  • 2 DOSAGE & ADMINISTRATION

    Valacyclovir tablets may be given without regard to meals.

    Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500 mg valacyclovir 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 valacyclovir 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 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 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 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-1–infected patients with a CD4+ cell count greater than or equal to 100 cells/mm3, the recommended dosage of
    valacyclovir tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.


    Reduction of Transmission: The recommended dosage of valacyclovir 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 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 tablets for the treatment of cold sores in pediatric patients aged greater than orequal 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 valacyclovir tablets 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
    valacyclovir 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 valacyclovir 500-mg tablets until a fine powder is produced (5
    valacyclovir tablets for 25-mg/mL suspension; 10 valacyclovir 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° to 8°C (36° 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 valacyclovir tablets in pediatric patients with a creatinine clearance <50 mL/min/1.73 m 2.

    Table 1. Valacyclovir Tablets 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 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 valacyclovir tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir 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 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 tablets should not be required following CAPD or CAVHD.

  • 3 DOSAGE FORMS & STRENGTHS

    Tablets:
    500 mg: blue, film-coated, capsule shaped tablets, debossed with 'I' on one side and '86' on other side.

  • 4 CONTRAINDICATIONS

    Valacyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)].

  • 5 WARNINGS AND PRECAUTIONS

    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 at doses of 8 grams per day. Treatment with valacyclovir hydrochloride 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 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 for their level of renal function. Dosage reduction is recommended when administering valacyclovir 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 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 for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].

  • 6 ADVERSE REACTIONS

    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)].

    The most common adverse reactions reported in at least 1 indication by greater than 10% of adult subjects treated with valacyclovir and observed more frequently with valacyclovir 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 of age was headache.

    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 trials for the treatment of cold sores, the adverse reactions reported by subjects receiving valacyclovir 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 valacyclovir 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 valacyclovir 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 valacyclovir 500 mg twice daily for 3 days (n = 402), valacyclovir 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 1 gram once daily (n = 269), valacyclovir 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 Patients: In HIV-1-infected patients, frequently reported adverse reactions for valacyclovir (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 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 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

    Laboratory Abnormality


    Herpes Zoster
    Genital Herpes Treatment
    Genital Herpes Suppression
    Valacyclovir

    1 gram

    3 Times

    Daily

    (n = 967)
    Placebo

    (n = 195)


    Valacyclovir

    1 gram

    Twice Daily

    (n = 1,194)
    Valacyclovir Hydrochloride

    500 mg

    twice daily

    (n = 1,159)
    Placebo

    (n = 439)


    Valacyclovir

    1 gram

    Once Daily

    (n = 269)


    Valacyclovir

    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/mm 3)
    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%

    a Data were not collected prospectively.

    LLN = Lower limit of normal.

    ULN = Upper limit of normal.




































    6.2 Clinical Trials Experience in Pediatric Patients

    The safety profile of valacyclovir 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 valacyclovir
    2 grams twice daily for 1 day, or valacyclovir 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 valacyclovir. 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.

    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:

    Erythema multiforme, rashes including photosensitivity, alopecia.

  • 7 DRUG INTERACTIONS

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

  • 8 USE IN SPECIFIC POPULATIONS

    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 valacyclovir 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 valacyclovir and any potential adverse effects on
    the breastfed child from valacyclovir or from the underlying maternal condition.


    Data
    Following oral administration of a 500-mg dose of valacyclovir 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
    valacyclovir 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

    Valacyclovir 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 valacyclovir 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 valacyclovir tablets 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 studies of valacyclovir, 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 to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

  • 10 OVERDOSAGE

    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)].

  • 11 DESCRIPTION

    Valacyclovir hydrochloride is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
    Valacyclovir tablets, USP are for oral administration. Each tablet contains valacyclovir hydrochloride USP equivalent to 500 mg or 1gm valacyclovir and the inactive ingredients crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. In addition to this 500 mg contains FD&C blue #2/ indigo carmine aluminum lake.
    The chemical name of valacyclovir hydrochloride is L-valine2-[(2-amino-1,6-dihydro-6-oxo-9 H-purin-9-yl)methoxy]ethyl ester hydrochloride monohydrate. It has the following structural formula:



    Structure

    Valacyclovir hydrochloride USP (monohydrate)is a white or almost white powder with the molecular formula C 13H 23N 6O 5Cl and a molecular weight of 378.81. Valacyclovir hydrochloride USP is freely soluble in water and practically insoluble in 1-octanol. The pka for valacyclovir hydrochloride is 5.95. Valacyclovir Tablets USP, 500 gm and 1 g complies with USP dissolution test 2.

  • 12 CLINICAL PHARMACOLOGY

    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 valacyclovir have been investigated in 14 volunteer trials involving 283 adults and in 3 studies involving 112 pediatric subjects from 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 valacyclovir 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 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 to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C max) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir 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 Valacyclovir to Healthy Adult Volunteers

    DoseSingle-Dose Administration

    (N = 8)
    Multiple-Dose Administration a

    (N = 24, 8 per treatment arm)
    C max (±SD)

    (mcg/mL)
    AUC (±SD)

    (hr●mcg/mL)
    C max (±SD) (mcg/mL) AUC (±SD) (hr●mcg/mL)
    100 mg0.83 (±0.14)2.28 (±0.40)NDND
    250 mg2.15 (±0.50)5.76 (±0.60)2.11 (±0.33)5.66 (±1.09)
    500 mg3.28 (±0.83)11.59 (±1.79)3.69 (±0.87)9.88 (±2.01)
    750 mg4.17 (±1.14)14.11 (±3.54)NDND
    1,000 mg5.65 (±2.37)19.52 (±6.04)4.96 (±0.64)15.70 (±2.27)

    a Administered 4 times daily for 11 days.

    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, 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 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 in volunteers with normal renal function.

    Specific Populations

    Patients with 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 to subjects 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 subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m 2 compared with 679.16 ± 162.76 mL/min/1.73 m 2 in healthy subjects.

    Patients with Hepatic Impairment: Administration of valacyclovir to subjects 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.

    Patients with HIV-1 Disease: In 9 subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm 3 who received valacyclovir 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 subjects.

    Geriatrics Patients: After single-dose administration of 1 gram of valacyclovir in healthy geriatric subjects, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir 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)].

    Pediatrics Patients:
    Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric subjects (aged 1 month to less than 12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.

    Table 4. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Patients vs. 1 Gram Single Dose of Valacyclovir to Adults

    ParameterPediatric Subjects (20 mg/kg Oral Suspension)Adults 1-gram Solid

    Dose of Valacyclovir a

    (n = 15)
    1 - <2 yr

    (n = 6)
    2 - <6 yr

    (n = 12)
    6 - <12 yr

    (n = 8)
    AUC (mcghr/mL)14.4 (±6.26)10.1 (±3.35)13.1 (±3.43)17.2 (±3.10)
    C max (mcg/mL) 4.03 (±1.37)3.75 (±1.14)4.71 (±1.20)4.72 (±1.37)

    a Historical estimates using pediatric pharmacokinetic sampling schedule.

    Drug Interaction Studies

    When valacyclovir is 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 is 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 (1 gram) were unchanged by coadministration of a single dose of antacids (Al 3+ or Mg ++).

    Cimetidine: Acyclovir C max and AUC following a single dose of valacyclovir (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

    Cimetidine Plus Probenecid: Acyclovir C max and AUC following a single dose of valacyclovir (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 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

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

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

    12.4 Microbiology

    Mechanism of Action:

    Valacyclovir is a deoxynucleoside 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.

    Acyclovir is a synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase
    (TK; pUL23) of HSV or VZV 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 α-herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of

    viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA
    polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient
    phosphorylation by the viral TK.

    Antiviral Activities

    The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC 50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC 50 values against herpes simplex virus isolates range from 0.09 to 60 microM (0.02 to 13.5 mcg/mL)for HSV-1 and from 0.04 to 44 microM (0.01 to 9.9 mcg/mL)for HSV-2. The EC 50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 microM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC 50 of 6 µM (1.35 mcg/mL).

    Resistance

    In Cell Culture: Acyclovir-resistant HSV-1, HSV-2, and VZV strains were isolated in cell culture. Acyclovir-resistant HSV and VZV
    resulted from mutations in the viral thymidine kinase (TK, pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were
    commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to
    acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity
    (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to
    phosphorylate thymidine (TK altered). In cell culture, acyclovir resistance-associated substitutions in TK of HSV-1 and HSV-2
    were observed (Table 5).

    Table 5. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions in Cell Culture
    VirusGeneSubstitution
    HSV-1TK

    P5A, H7Q, L50V, G56V, G59R/V/W/A, G61A/V, K62I/N, T63A, E83K, P84L/S, R89W, D116N, P131S,
    P155R, F161I/C, R163H/P, A167V, P173L, R176Q/W, Q185R, A189L/V, G200S, G206R, R216S, R220H,
    L227F, Y239S, T245M, Q261stop, R281stop, T287M, M322K, C336Y, V348A

    HSV-2TKL69P, C172R, A175V, T288M
    HSV-1POLD368A, Y557S, E597D, V621S, L702H, A719V, S742N, N815S, V817M, Y818C, G841C/S
    HSV-2POLNo substitutions detected

    HSV-Infected Patients: Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their €-herpes virus
    infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 6).
    HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of
    substitutions in the HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes
    will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral
    resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during
    therapy.

    Table 6. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Observed in Treated Patients
    VirusGeneSubstitution
    HSV-1TKG6C, R32H, R41H, R51W, Y53C/D/H, Y53stop, D55N, G56D/E/S, P57H, G58N/R, G59R, G61A/E/W,
    K62N, T63I, Q67stop, S74stop, Y80N, E83K, P84L, Y87H, E95stop, T103P, Q104H, Q104stop, H105P,
    M121K/L/R, Q125N, M128L, G129D, I143V, A156V, D162A/H/N, R163G/H, L170P, Y172C, P173L/R,
    A174P, A175V, R176Q/W, R176stop, L178R, S181N, A186P, V187M, A189V, V192A, G200C/D/S, T201P,
    T202A, V204G, A207P, L208F/H, R216C/H, R220C/H, R221C/H, R222C/H, E226K, D229H, L242P,
    T245M/P, L249P, Q250stop, C251G, E257K, Q261R, A265T, R281stop, T287M, L288stop, L291R,
    L297S, L315S, L327R, C336Y, C336stop, Q342stop, T354P, L364P, A365T
    HSV-2TKG25A, R34C, G39E, R51W, Y53N/D, G59P, G61A/E/W, S66P, A72S, D78N, P85S, R86P, A94V, L98stop,
    N100H, I101S, Q103stop, Q105P, A125T, T131P, Y133F, D137stop, F140L, L158P, S169P, R177W,
    S182N, M183Istop, V192M, G201D, R217H, R221C/H, Q222stop, R223H, D229stop, Y239stop, D231N,
    L263stop, R271V, P272S, D273R, T287M, C337Y
    HSV-1POLK532T, S559L, Q570R, L583V, A605V, V621S, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q,
    S775N, L778M, E798K, V813M, N815S, G841S, R842S, I890M, V958L, H1228D
    HSV-2POL

    E250Q, D307N, K533E, A606V, C625R, R628C, E678G, A724V, S725G, S729N, I731F, Q732R, D785N,
    M789K/T, V818A, N820S, Y823C, Q829R, T843A, M910T, D912N/V, A915V, F923L, T934A, R964H

    Note: Many additional pathways to acyclovir resistance likely exist.


    Cross-Resistance
    Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated
    substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) (Table 7).

    Table 7. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS
    Cross-Resistant
    Drug
    Virus/GeneSubstitution
    PCV/FCVHSV-1 TKG6C, R32H, R51W, Y53C/H/N, H58N, G61A, S74stop, E83K, P84L, T103P, Q104stop,
    D116N, M121R, I143V, P155R, R163G/H, A167V, L170P, Y172C, P173L, A174P, R176Q/W,
    Q185R, A186P, A189L/V, G200D/S, G206R, L208H, R216C, R220H, R222C/H, Y239S,
    T245M, Q250stop, Q261stop, R281stop, T287M, L315S, M322K, C336Y, V348A
    HSV-1 POLA657T, D672N, V715G, A719V, S724N, E798K, N815S, G841C/S
    HSV-2 TKG39E, R51W, Y53N, R86P, Y133F, R177W, R221H, T288M
    HSV-2 POLK533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934A
    FOSHSV-1 POLD368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S,
    V817M, G841C/S, I890M
    HSV-2 POLK533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A,
    Y823C, D912V, F923L, T934A, R964H

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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

    Carcinogenesis

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

    Mutagenesis

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

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

    Valacyclovir was mutagenic in a mouse micronucleus assay.

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

  • 14 CLINICAL STUDIES

    14.1 Cold Sores (Herpes Labialis)

    Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (aged greater
    than or equal to 12 years) with a history of recurrent cold sores. Subjects self-initiated therapy at the earliest symptoms and
    prior to any signs of a cold sore. The majority of subjects initiated treatment within 2 hours of onset of symptoms. Subjects
    were randomized to valacyclovir 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir 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 or placebo in the prevention of progression of
    cold sore lesions beyond the papular stage.

    14.2 Genital Herpes Infections

    Initial Episode

    Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 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. Subjects self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

    In 1 study, subjects were randomized to receive 5 days of treatment with either valacyclovir 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in subjects with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir 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 500 mg twice daily for 5 days (n = 398) or valacyclovir 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-1-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 8.

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

    Outcome
    6 Months
    12 Months
    Valacyclovir

    1 gram

    Once Daily

    (n = 269)

    Oral Acyclovir

    400 mg

    Twice Daily

    (n = 267)

    Placebo

    (n = 134)

    Valacyclovir

    1 gram

    Once Daily

    (n = 269)

    Oral Acyclovir

    400 mg

    Twice Daily

    (n = 267)

    Placebo

    (n = 134)

    Recurrence free
    55%
    54%
    7%
    34%
    34%
    4%
    Recurrences
    35%
    36%
    83%
    46%
    46%
    85%
    Unknown a
    10%
    10%
    10%
    19%
    19%
    10%

    a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

    Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir 500 mg once daily.

    In a second study, 293 HIV-1-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir 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 log 10 copies/mL. Among subjects who received valacyclovir, the prestudy median CD4+ cell count was 336 cells/mm 3; 11% had less than100 cells/mm 3, 16% had 100 to 199 cells/mm 3, 42% had 200 to 499 cells/mm 3, and 31% had greater than or equal to 500 cells/mm 3. Outcomes for the overall study population are shown in Table 9.

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

    Outcome
    Valacyclovir

    500 mg Twice Daily

    (n = 194)

    Placebo

    (n = 99)

    Recurrence free
    65%
    26%
    Recurrences
    17%
    57%
    Unknown a
    18%
    17%

    a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

    Reduction of Transmission of Genital Herpes

    A double-blind, placebo-controlled trial 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 trial period. Source partners were randomized to treatment with either valacyclovir 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 10.

    Table 10. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints

    Endpoint
    Valacyclovir a

    (n = 743)

    Placebo

    (n = 741)

    Symptomatic HSV-2 acquisition
    4 (0.5%)
    16 (2.2%)
    HSV-2 seroconversion
    12 (1.6%)
    24 (3.2%)
    Overall HSV-2 acquisition
    14 (1.9%)
    27 (3.6%)

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

    14.3 Herpes Zoster

    Two randomized, double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted.
    Valacyclovir was compared with placebo in subjects aged less than 50 years and with oral acyclovir in subjects aged greater
    than 50 years. All subjects were treated within 72 hours of appearance of zoster rash. In subjects aged less than 50 years,
    the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir compared with 3 days forthose treated with placebo. In subjects aged greater than 50 years, the median time to cessation of new lesions was 3 days
    in subjects treated with either valacyclovir or oral acyclovir. In subjects aged less than 50 years, no difference was found with
    respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir and placebo. In
    subjects aged greater than 50 years, among the 83% who reported pain after healing (post-herpetic neuralgia), the median
    duration of pain after healing (95% CI) in days was: 40 (31, 51), 43 (36, 55), and 59 (41, 77) for 7-day valacyclovir, 14-day
    valacyclovir, and 7-day oral acyclovir, respectively.

    14.4 Chickenpox

    The use of valacyclovir for treatment of chickenpox in pediatric subjects 2 to less than 18 years of 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 subjects.

    The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric subjects 1 to less than 12 years 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 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 herpes zoster. The mean projected daily acyclovir exposures in pediatric subjects across all age-groups (1 to less than 12 years) 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 subjects were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric subjects 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 less than 18 years.
    Because the efficacy and safety of acyclovir for the treatment of chickenpox in children aged less than 2 years have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children aged less than 2 years with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days'

    duration are not available [see Use in Specific Populations (8.4)].

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Valacyclovir Tablets USP, 500 mg are blue, film-coated, capsule shaped tablets, debossed with 'I' on one side and '86' on
    other side. They are supplied in


    Boxes of 10 x 10 UD 100's NDC: 63739-077-10


    Storage:
    Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed container as defined in
    the USP.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Patient Information).

    Importance of Adequate Hydration

    Patients should be advised to maintain adequate hydration.

    Missed Dose

    Instruct patients that if they miss a dose of valacyclovir, to take it as soon as they remember. Advise patients not to double
    their next dose or take more than the prescribed dose.

    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 is not a cure for cold sores.

    Genital Herpes

    Patients should be informed that valacyclovir is 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. 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 has 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-1-infected patients.

    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.

    Chickenpox

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

    Manufactured By: Hetero™
    Hetero Labs Limited, Unit V, Polepally, Jadcherla,
    Mahabubnagar-509 301, India.


    Distributed by:
    McKesson Corporation dba SKY Packaging
    Memphis, TN 38141


    Revised: 11/2021


    21559

  • PATIENT INFORMATION

    What are valacyclovir tablets?
    Valacyclovir tablets are a prescription medicine used in adults:

    to treat cold sores (herpes labialis).
    to treat or control genital herpes outbreaks in adults with normal
    immune systems.
    to control genital herpes outbreaks in adults with human
    immunodeficiency virus-1 (HIV-1).
    with safer sex practices to lower the chance of spreading genital herpes
    to others, in adults with normal immune systems. Even with safer sex
    practices, it is still possible to spread genital herpes.
    ° Do not have sexual contact with your partner when you have any
    symptom or outbreak of genital herpes.

    ° Use a condom made of latex or polyurethane whenever you have
    sexual contact.
    ° Ask your healthcare provider for more information about safer sex
    practices.
    to treat shingles (herpes zoster) in adults with normal immune systems.

    Valacyclovir tablets are used in children to treat:
    cold sores in children 12 years of age and older.
    chickenpox in children with normal immune systems 2 years of age to
    less than 18 years of age.
    Valacyclovir tablets does not cure cold sores, chickenpox, shingles, or
    genital herpes.
    It is not known if valacyclovir tablets are safe and effective in people
    with weakened immune systems, other than for control of outbreaks of
    genital herpes in people with HIV-1.
    It is not known if valacyclovir tablets are safe and effective in people 18
    years of age and older with chickenpox.
    It is not known if valacyclovir tablets are safe and effective in children:
    ° less than 12 years of age with cold sores
    ° less than 2 years of age with chickenpox
    ° less than 18 years of age with genital herpes or shingles

    Do not take valacyclovir tablets if you are allergic to valacyclovir,
    acyclovir, or any of the ingredients in valacyclovir tablets.
    See the end of this leaflet for a complete list of ingredients in valacyclovir
    tablets.


    Before you take valacyclovir tablets, tell your healthcare provider
    about all of your medical conditions, including if you:

    have had a bone marrow transplant or kidney transplant, or if you have
    advanced HIV-1 infection or acquired immune deficiency syndrome
    (AIDS).
    have kidney problems, including if you receive dialysis.

    are pregnant or plan to become pregnant. It is not known if valacyclovir
    tablets will harm your unborn baby. You and your healthcare provider will
    decide if you will take valacyclovir tablets if you are pregnant.
    are breastfeeding or plan to breastfeed. valacyclovir may pass into your
    breastmilk. Talk with your healthcare provider about the best way to feed
    your child if you take valacyclovir tablets.

    Tell your healthcare provider about all the medicines you take,
    including prescription and over-the-counter medicines, vitamins, and
    herbal supplements.

    How should I take valacyclovir tablets?
    Take valacyclovir tablets exactly as your healthcare provider tells you to
    take it.
    Your dose of valacyclovir tablets and length of treatment will depend on
    the type of infection that you have and any other medical problems that
    you have.
    Do not stop valacyclovir tablets or change your treatment without talking
    to your healthcare provider.
    Take valacyclovir tablets with or without food.
    Tell your healthcare provider if your child cannot swallow valacyclovir
    tablets tablets. Your healthcare provider can prescribe valacyclovir
    tablets as an oral suspension for your child.
    If you are taking valacyclovir tablets to treat outbreaks of cold sores,
    chickenpox, shingles, or genital herpes, take valacyclovir tablets as soon
    as you have the first symptoms of infection such as tingling, itching, or
    burning, or when the sore appears.
    It is important for you to stay well hydrated during treatment with
    valacyclovir tablets. Be sure to drink plenty of fluids during this time.
    If you miss a dose of valacyclovir tablets, take it as soon as you
    remember. If it is almost time for your next dose, do not take the missed
    dose. Take the next dose at your regular time. Do not take 2 doses at the
    same time or take more valacyclovir tablets than prescribed.
    If you take too much valacyclovir tablets, call your healthcare provider or
    go to the nearest hospital emergency room right away.

    What are the possible side effects of valacyclovir tablets?
    Valacyclovir tablets can cause serious side effects including:
    Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic
    Syndrome (HUS).
    TTP and HUS have happened in people with
    weakened immune systems taking valacyclovir and have led to death.
    TTP and HUS are disorders that can cause small blood clots to form
    throughout the body and decrease blood flow to body organs such as
    the brain, heart, and kidneys. Your healthcare provider will stop
    treatment with valacyclovir tablets if you have signs or symptoms of TTP
    and HUS.
    kidney failure.
    nervous system problems. Tell your healthcare provider right away if
    you get any of these signs or symptoms of nervous system problems
    during treatment with valacyclovir tablets:
    ° aggressive behavior ° speech problems
    ° unsteady movement ° hallucinations (seeing or hearing things
    that are really not there)
    ° shaky movements ° seizures
    ° confusion ° coma
    Elderly people are more likely to get certain side effects. Talk to your

    healthcare provider if this is a concern for you.
    The most common side effects of valacyclovir tablets in adults
    include:
    headache stomach (abdominal) pain
    nausea
    The most common side effect of valacyclovir tablets in children less
    than 18 years of age is headache.

    These are not all the possible side effects of valacyclovir tablets.
    Call your doctor for medical advice about side effects. You may report side
    effects to FDA at 1-800-FDA-1088.

    How should I store valacyclovir tablets?
    Store valacyclovir tablets at room temperature, 68° to 77°F (20° to
    25°C).
    Keep valacyclovir in a tightly closed container.
    Keep valacyclovir tablets and all medicines out of the reach of children.
    General information about the safe and effective use of valacyclovir
    tablets.

    Medicines are sometimes prescribed for purposes other than those listed in
    a Patient Information leaflet. Do not use valacyclovir tablets for a condition
    for which it was not prescribed. Do not give valacyclovir tablets to other
    people, even if they have the same symptoms that you have. It may harm
    them. You can ask your healthcare provider or pharmacist for information
    about valacyclovir tablets that is written for health professionals.
    For more information, call 1-866-495-1995.

    What are the ingredients in valacyclovir?
    Active Ingredient: valacyclovir hydrochloride USP (monohydrate)
    Inactive Ingredients: crospovidone, FD&C blue #2/ indigo carmine
    aluminum lake, hypromellose, magnesium stearate, microcrystalline
    cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium
    dioxide.
    This Patient Information has been approved by the U.S. Food and Drug
    Administration.
    Patient Information available at http://camberpharma.com/medication-guides


    Manufactured By: Hetero™
    Hetero Labs Limited, Unit V, Polepally, Jadcherla,
    Mahabubnagar-509 301, India.


    Distributed by:
    McKesson Corporation dba SKY Packaging
    Memphis, TN 38141


    Revised: 11/2021 2065245
    21559

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    500 mg

    PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

  • INGREDIENTS AND APPEARANCE
    VALACYCLOVIR 
    valacyclovir tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 63739-077(NDC:31722-704)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    VALACYCLOVIR HYDROCHLORIDE (UNII: G447S0T1VC) (ACYCLOVIR - UNII:X4HES1O11F) VALACYCLOVIR500 mg
    Inactive Ingredients
    Ingredient NameStrength
    CROSPOVIDONE (UNII: 68401960MK)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
    POVIDONE (UNII: FZ989GH94E)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    ColorblueScoreno score
    ShapeCAPSULESize18mm
    FlavorImprint Code I;86
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 63739-077-1010 in 1 BOX, UNIT-DOSE03/17/2022
    110 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20304703/17/2022
    Labeler - McKesson Corporation dba SKY Packaging (140529962)
    Establishment
    NameAddressID/FEIBusiness Operations
    Legacy Pharmaceutical Packaging, LLC143213275repack(63739-077) , relabel(63739-077)

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