Valacyclovir
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Valacyclovir Prescribing Information
Valacyclovir tablet is a deoxynucleoside analogue DNA polymerase inhibitor indicated for:
Adult Patients (
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.
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.)
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.
• Cold Sores (Herpes Labialis)
• Genital Herpes
• Treatment in immunocompetent patients (initial or recurrent episode)
• Suppression in immunocompetent or HIV-1-infected patients
• Reduction of transmission
• Herpes Zoster
Pediatric Patients (
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.
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)
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 ].
• Cold Sores (Herpes Labialis)
• Chickenpox
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.
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.
• 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 (
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.
• 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.)].
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.
Tablets:
• 500 mg: blue, film-coated, capsule shaped tablets, debossed with 'I' on one side and '86' on other side.
• 1 gm: white to off-white, film-coated, capsule shaped tablets, debossed with 'I' on one side and '87' on other side with partial scorebar on both sides.
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.
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 (
Facial edema, hypertension, tachycardia.
Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria
Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and
visual hallucinations, seizures, tremors
Visual abnormalities.
Diarrhea.
Liver enzyme abnormalities, hepatitis.
Renal failure, renal pain (may be associated with renal failure)
Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS
Erythema multiforme, rashes including photosensitivity, alopecia.)].
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 ].
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 , Use in Specific Populations ].
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 , Use in Specific Populations ].
Hematologic
Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS
[see Warnings and Precautions ]
.Skin
Erythema multiforme, rashes including photosensitivity, alopecia.
• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV-1 disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (
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 valacyclovir at doses of 8 grams per day. Treatment with valacyclovir should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
• Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher- than-recommended doses of valacyclovir for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (
Dosage recommendations for adult patients with reduced renal function are provided in Table 1
[see Use in Specific Populations , Clinical Pharmacology (12.3)].
Data are not available for the use of valacyclovir tablets in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m2.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 to 49 | 10 to 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 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.
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 , Use in Specific Populations ].
• 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 , Use in Specific Populations ].
• 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 , Adverse Reactions ].
• Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher-than-recommended doses of valacyclovir for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (
Dosage recommendations for adult patients with reduced renal function are provided in Table 1
[see Use in Specific Populations , Clinical Pharmacology (12.3)].
Data are not available for the use of valacyclovir tablets in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m2.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 to 49 | 10 to 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 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.
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 , Use in Specific Populations ].
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