Valtrex Drug Information

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). The total dose should not exceed 1 gram 3 times daily.

Extemporaneous Preparation of Oral Suspension Ingredients and Preparation per USP ‑ NF VALTREX tablets 500 mg, cherry flavor, and Suspension Structured Vehicle USP-NF (SSV). Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of 100 mL. Instructions for Preparing Suspension at Time of Dispensing Prepare SSV according to the USP-NF.

Using a pestle and mortar, grind the required number of VALTREX 500-mg tablets until a fine powder is produced (5 VALTREX tablets for 25-mg/mL suspension; 10 VALTREX tablets for 50-mg/mL suspension). Gradually add approximately 5-mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted.

Continue to add approximately 5-mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50-mg/mL suspensions. Transfer the mixture to a suitable 100-mL measuring flask. Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV.

Once dissolved, add to the measuring flask. Rinse the mortar at least 3 times with approximately 5-mL aliquots of SSV, transferring the rinsing to the measuring flask between additions. Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix.

Transfer the suspension to an amber glass medicine bottle with a child-resistant closure. The prepared suspension should be labeled with the following information “Shake well before using. Store suspension between 2°C to 8°C (36°F to 46°F) in a refrigerator.

Discard after 28 days.” *The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.

Patients with Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1. Data are not available for the use of VALTREX in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m 2. Table 1.

VALTREX Dosage Recommendations for Adults with Renal Impairment 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.

Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for subjects receiving VALTREX compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.

For the incidence of laboratory abnormalities see Table 2. Table 2. 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. 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. 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.

Eye Visual abnormalities. Gastrointestinal Diarrhea. Hepatobiliary Tract and Pancreas Liver enzyme abnormalities, hepatitis.

Renal Renal failure, renal pain (may be associated with renal failure). Hematologic Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS. Skin and Subcutaneous Tissue Disorders Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), Stevens‑Johnson syndrome (SJS), erythema multiforme (EM), rashes including photosensitivity, alopecia.

No clinically significant drug-drug or drug-food interactions with VALTREX are known.

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 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. The Acyclovir and the Valacyclovir Pregnancy Registries, both population-based international prospective studies, collected pregnancy data through April 1999.

The occurrence of major birth defects during first-trimester exposure to acyclovir was and during any trimester of exposure was 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 and during any trimester of exposure was 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. 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.

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. 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. The use of VALTREX for treatment of chickenpox in pediatric patients aged 2 to less than 18 years is based on single‑dose pharmacokinetic and multiple‑dose safety data from an open‑label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double‑blind, placebo‑controlled trials evaluating oral acyclovir in pediatric subjects with chickenpox.

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 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 (C max: ↑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. 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. 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.

VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction to valacyclovir, acyclovir, or any component of the formulation. Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any component of the formulation.

Caution should be exercised to prevent inadvertent overdose. 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.