Adult Patients
Cold Sores (Herpes Labialis): Valtrex® (valacyclovir hydrochloride) Caplets are indicated for treatment of cold sores (herpes labialis). The efficacy of Valtrex initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.
Genital Herpes: Initial Episode: Valtrex is indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with Valtrex when initiated more than 72 hours after the onset of signs and symptoms has not been established.
Recurrent Episodes: Valtrex is indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with Valtrex when initiated more than 24 hours after the onset of signs and symptoms has not been established.
Suppressive Therapy: Valtrex is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-1 infected adults. The efficacy and safety of Valtrex for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-1 infected patients have not been established.
Reduction of Transmission: Valtrex is indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of Valtrex for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of Valtrex for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines).
Herpes Zoster: Valtrex is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of Valtrex when initiated more than 72 hours after the onset of rash and the efficacy and safety of Valtrex for treatment of disseminated herpes zoster have not been established.
Pediatric Patients
Cold Sores (Herpes Labialis): Valtrex is indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years. The efficacy of Valtrex initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.
Chickenpox: Valtrex is indicated for the treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years. Based on efficacy data from clinical studies with oral acyclovir, treatment with Valtrex should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4)].
Limitations of Use
The efficacy and safety of Valtrex have not been established in:
- Immunocompromised patients other than for the suppression of genital herpes in HIV-1 infected patients with a CD4+ cell count greater than or equal to 100 cells/mm3.
- Patients aged less than 12 years with cold sores (herpes labialis).
- Patients aged less than 2 years or greater than or equal to 18 years with chickenpox.
- Patients aged less than 18 years with genital herpes.
- Patients aged less than 18 years with herpes zoster.
- Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.
Valtrex Dosage and Administration
- Valtrex may be given without regard to meals.
- Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500 mg Valtrex Caplets for use in pediatric patients for whom a solid dosage form is not appropriate [see Dosage and Administration (2.3)].
Adult Dosing Recommendations
Cold Sores (Herpes Labialis): The recommended dosage of Valtrex for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
Genital Herpes: Initial Episode: The recommended dosage of Valtrex for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
Recurrent Episodes: The recommended dosage of Valtrex for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.
Suppressive Therapy: The recommended dosage of Valtrex for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.
In HIV-1 infected patients with a CD4+ cell count greater than or equal to 100 cells/mm3, the recommended dosage of Valtrex for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
Reduction of Transmission: The recommended dosage of Valtrex for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.
Herpes Zoster: The recommended dosage of Valtrex for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.
Pediatric Dosing Recommendations
Cold Sores (Herpes Labialis): The recommended dosage of Valtrex for the treatment of cold sores in pediatric patients aged greater than or equal to 12 years is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
Chickenpox: The recommended dosage of Valtrex for treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)].
Extemporaneous Preparation of Oral Suspension
Ingredients and Preparation per USP-NF: Valtrex Caplets 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 Suspension at Time of Dispensing as Follows:
- Prepare SSV according to the USP-NF.
- Using a pestle and mortar, grind the required number of Valtrex 500 mg Caplets until a fine powder is produced (5 Valtrex Caplets for 25 mg/mL suspension; 10 Valtrex Caplets 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.
Patients With Renal Impairment
Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of Valtrex in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m2.
Table 1. Valtrex Dosage Recommendations for Adults With Renal Impairment
| Indications |
Normal Dosage Regimen (Creatinine Clearance ≥50 mL/min) |
Creatinine Clearance (mL/min) |
| 30-49 |
10-29 |
<10 |
|
|
Cold sores (Herpes labialis)
Do not exceed 1 day of treatment. |
Two 2 gram doses taken 12 hours apart |
Two 1 gram doses taken 12 hours apart |
Two 500 mg doses taken 12 hours apart |
500 mg single dose |
Genital herpes:
Initial episode |
1 gram every 12 hours |
no reduction |
1 gram every 24 hours |
500 mg every 24 hours |
Genital herpes:
Recurrent episode |
500 mg every 12 hours |
no reduction |
500 mg every 24 hours |
500 mg every 24 hours |
Genital herpes:
Suppressive therapy |
|
|
|
|
Immunocompetent patients
|
1 gram every 24 hours |
no reduction |
500 mg every 24 hours |
500 mg every 24 hours |
Alternate dose for immunocompetent patients with greater than or equal to 9 recurrences/year
|
500 mg every 24 hours |
no reduction |
500 mg every 48 hours |
500 mg every 48 hours |
| HIV-1 infected patients |
500 mg every 12 hours |
no reduction |
500 mg every 24 hours |
500 mg every 24 hours |
| Herpes zoster |
1 gram every 8 hours |
1 gram every 12 hours |
1 gram every 24 hours |
500 mg every 24 hours |
Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of Valtrex after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of Valtrex is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.
Peritoneal Dialysis: There is no information specific to administration of Valtrex in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of Valtrex should not be required following CAPD or CAVHD.
Dosage Forms and Strengths
Caplets:
- 500-mg: blue, film-coated, capsule-shaped tablets printed with "Valtrex 500 mg."
- 1-gram: blue, film-coated, capsule-shaped tablets, with a partial scorebar on both sides, printed with "Valtrex 1 gram."
Contraindications
Valtrex is 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)].
Warnings and Precautions
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valtrex at doses of 8 grams per day. Treatment with Valtrex should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
Acute Renal Failure
Cases of acute renal failure have been reported in:
- Elderly patients with or without reduced renal function. Caution should be exercised when administering Valtrex to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4), Use in Specific Populations (8.5)].
- Patients with underlying renal disease who received higher than recommended doses of Valtrex for their level of renal function. Dosage reduction is recommended when administering Valtrex to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].
- Patients receiving other nephrotoxic drugs. Caution should be exercised when administering Valtrex to patients receiving potentially nephrotoxic drugs.
- Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4), Adverse Reactions (6.3)].
Central Nervous System Effects
Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of Valtrex for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valtrex should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].
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 patients treated with Valtrex and observed more frequently with Valtrex compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric patients aged less than 18 years was headache.
Clinical Trials Experience in Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving Valtrex 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for patients receiving Valtrex compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.
Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by greater than or equal to 5% of patients receiving Valtrex 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.
Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of patients receiving Valtrex 500 mg twice daily for 3 days (n = 402), Valtrex 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.
Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving Valtrex 1 gram once daily (n = 269), Valtrex 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.
Suppression of Recurrent Genital Herpes in HIV-1 Infected Patients: In HIV-1 infected patients, frequently reported adverse reactions for Valtrex (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.
Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving Valtrex 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).
Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving Valtrex 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.
Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations
| Laboratory Abnormality |
Herpes Zoster |
Genital Herpes Treatment |
Genital Herpes Suppression |
Valtrex
1 gram
3 times daily
(n = 967) |
Placebo
(n = 195) |
Valtrex
1 gram twice daily
(n = 1,194) |
Valtrex
500 mg twice daily
(n = 1,159) |
Placebo
(n = 439) |
Valtrex
1 gram once daily
(n = 269) |
Valtrex
500 mg once daily
(n = 266) |
Placebo
(n = 134) |
|
Hemoglobin
(<0.8 x LLN) |
0.8% |
0% |
0.3% |
0.2% |
0% |
0% |
0.8% |
0.8% |
White blood cells
(<0.75 x LLN) |
1.3% |
0.6% |
0.7% |
0.6% |
0.2% |
0.7% |
0.8% |
1.5% |
| Platelet count (<100,000/mm3) |
1.0% |
1.2% |
0.3% |
0.1% |
0.7% |
0.4% |
1.1% |
1.5% |
AST (SGOT)
(>2 x ULN) |
1.0% |
0% |
1.0% |
a |
0.5% |
4.1% |
3.8% |
3.0% |
Serum creatinine
(>1.5 x ULN) |
0.2% |
0% |
0.7% |
0% |
0% |
0% |
0% |
0% |
| a Data were not collected prospectively. |
| LLN = Lower limit of normal. |
| ULN = Upper limit of normal. |
Clinical Trials Experience in Pediatric Patients
The safety profile of Valtrex has been studied in 177 pediatric patients aged 1 month to less than 18 years. Sixty-five of these pediatric patients, aged 12 to less than 18 years, received oral caplets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.
Pediatric Patients Aged 12 to Less Than 18 Years (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving Valtrex 2 grams twice daily for 1 day, or Valtrex 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
Pediatric Patients Aged 1 Month to Less Than 12 Years: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies 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.
Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Valtrex. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Valtrex.
General: Facial edema, hypertension, tachycardia.
Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)].
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.
Drug Interactions
No clinically significant drug-drug or drug-food interactions with Valtrex are known [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B. There are no adequate and well-controlled studies of Valtrex or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Valtrex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
Nursing Mothers
Following oral administration of a 500 mg dose of Valtrex to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of Valtrex twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when Valtrex is administered to a nursing woman.
Pediatric Use
Valtrex is indicated for treatment of cold sores in pediatric patients aged greater than or equal to 12 years and for treatment of chickenpox in pediatric patients aged 2 to less than 18 years [see Indications and Usage (1.2), Dosage and Administration (2.2)].
The use of Valtrex for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores [see Clinical Studies (14.1)].
The use of Valtrex for treatment of chickenpox in pediatric patients aged 2 to less than 18 years is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].
The efficacy and safety of valacyclovir have not been established in pediatric patients:
- 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 studies. No efficacy evaluations were conducted in any of the 3 studies.
Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 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)].
Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 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.
Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients aged 1 to less than 12 years with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to 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.
Of the total number of subjects in clinical studies of Valtrex, 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)].
Renal Impairment
Dosage reduction is recommended when administering Valtrex to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].
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)].
Valtrex Description
Valtrex (valacyclovir hydrochloride) is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
Valtrex Caplets are for oral administration. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.
The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C13H20N6O4•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pkas for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
Valtrex - Clinical Pharmacology
Mechanism of Action
Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].
Pharmacokinetics
The pharmacokinetics of valacyclovir and acyclovir after oral administration of Valtrex have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects aged 1 month to less than 12 years.
Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
The absolute bioavailability of acyclovir after administration of Valtrex is 54.5% ± 9.1% as determined following a 1-gram oral dose of Valtrex and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valtrex is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
Acyclovir pharmacokinetic parameter estimates following administration of Valtrex to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of Valtrex from doses between 250 mg to 1 gram.
There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.
Table 3. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valtrex to Healthy Adult Volunteers
| Dose |
Single-Dose Administration
(N = 8) |
Multiple-Dose Administrationa
(N = 24, 8 per treatment arm) |
Cmax (±SD)
(mcg/mL) |
AUC (±SD) (hr●mcg/mL) |
Cmax (±SD) (mcg/mL) |
AUC (±SD) (hr●mcg/mL) |
|
| 100 mg |
0.83 (±0.14) |
2.28 (±0.40) |
ND |
ND |
| 250 mg |
2.15 (±0.50) |
5.76 (±0.60) |
2.11 (±0.33) |
5.66 (±1.09) |
| 500 mg |
3.28 (±0.83) |
11.59 (±1.79) |
3.69 (±0.87) |
9.88 (±2.01) |
| 750 mg |
4.17 (±1.14) |
14.11 (±3.54) |
ND |
ND |
| 1,000 mg |
5.65 (±2.37) |
19.52 (±6.04) |
4.96 (±0.64) |
15.70 (±2.27) |
| 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 Valtrex, 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 Valtrex 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 Valtrex in volunteers with normal renal function.
Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)].
Following administration of Valtrex to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one-third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Hepatic Impairment: Administration of Valtrex to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
HIV-1 Disease: In 9 patients with HIV-1 disease and CD4+ cell counts less than 150 cells/mm3 who received Valtrex at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.
Geriatrics: After single-dose administration of 1 gram of Valtrex in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of Valtrex 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 Po
