The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, 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 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 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 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. 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 hydrochloride.
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.
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.
No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3)].
pregnancy Category B. There are no adequate and well-controlled studies of valacyclovir hydrochloride 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. Valacyclovir hydrochloride 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.
Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 nursing mothers, peak acyclovir concentrations (C max ) 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride is administered to a nursing woman.
Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age [see Indications and Usage(1.2, Dosage and Administration (2.2)].
The use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)].
The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age 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:
• <12 years of age with cold sores
• <18 years of age with genital herpes
• <18 years of age with herpes zoster
• <2 years of age with chickenpox
• for suppressive therapy following neonatal HSV infection.
The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age 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 1 to <12 years of age 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 1 month to <6 years of age 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 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, 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 1 to <12 years of age 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 <12 years of age) 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 1 to <12 years of age with recurrent genital herpes.
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