6.2 Clinical Trials Experience in Pediatric Patients

Sixty-five pediatric patients, 12 to < 18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. 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%).

Labeling describing additional clinical trial adverse reactions in pediatric patients (ages of 1 month to ≤ 12 years) is approved for GlaxoSmithKline’s Valtrex ® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those adverse reactions is not approved for this valacyclovir HCL tablet product.

6.3 Postmarketing Experience

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.

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.


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


8.1 Pregnancy

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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥ 12 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 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
  • for suppressive therapy following neonatal HSV infection.

In infants 1 month to < 3 months of age, 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.

Labeling describing pediatric use information in pediatric patients with chickenpox (ages 2 to ≤18 years) and additional pharmacokinetic studies in pediatric patients (ages 3 months to < 12 years) treated with valacyclovir HCL is approved for GlaxoSmithKline’s Valtrex ® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, that additional pediatric information is not approved for this valacyclovir HCL tablet product.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of valacyclovir hydrochloride, 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 hydrochloride to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

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