Valacyclovir (Page 3 of 8)

6.2 Clinical Trials Experience in Pediatric Patients

The safety profile of valacyclovir has been studied in 177 pediatric subjects aged 1 month to less than 18 years. Sixty-five of
these pediatric subjects, aged 12 to less than 18 years, received oral tablets for 1 to 2 days for treatment of cold sores. The
remaining 112 pediatric subjects, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety trials and
received valacyclovir oral suspension. 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.


Pediatric Subjects Aged 12 to Less than 18 Years (Cold Sores)
In clinical trials for the treatment of cold sores, the adverse reactions reported by adolescent subjects receiving valacyclovir
2 grams twice daily for 1 day, or valacyclovir 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 Subjects Aged 1 Month to Less than 12 Years
Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials 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.

6.3 Postmarketing Experience

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 (4)].
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 (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.

7 DRUG INTERACTIONS

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

8 USE IN SPECIFIC POPULATIONS

8.1 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 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.

8.2 Lactation

Risk Summary
Although there is no information on the presence of valacyclovir in human milk, its metabolite, acyclovir, is present in human
milk following oral administration of valacyclovir. Based on published data, a 500-mg maternal dose of valacyclovir twice daily
would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day (see Data). There is no data on
the effects of valacyclovir or acyclovir on the breastfed child or on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for valacyclovir and any potential adverse effects on
the breastfed child from valacyclovir or from the underlying maternal condition.


Data
Following oral administration of a 500-mg dose of valacyclovir to 5 lactating women, 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 dose of
valacyclovir twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day.
Unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine.

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