Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

VALTREX (NDA-020487)

(VALACYCLOVIR HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/10/2019 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

‘Subjects’ replace ‘Patients’ throughout section.

‘Trial’ replaces ‘Study’ throughout section.

8 Use in Specific Populations

8.1 Pregnancy

‘Subjects’ replace ‘Patients’ throughout section.

‘Trial’ replaces ‘Study’ throughout section.

PLLR conversion; additions and/or revisions underlined:

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

PLLR conversion; additions and/or revisions underlined:

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 VALTREX 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 VALTREX and any potential adverse effects on the breastfed child from VALTREX or from the underlying maternal condition.

Data

Following oral administration of a 500-mg dose of VALTREX 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 VALTREX 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Missed Dose

Instruct patients that if they miss a dose of VALTREX, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

PATIENT INFORMATION

Additions and/or revisions underlined:

What is VALTREX?

VALTREX is a prescription medicine used in adults:

with safer sex practices to lower the chance of spreading genital herpes to others, in adults with normal immune systems. Even with safer sex practices, it is still possible to spread genital herpes.

VALTREX does not cure herpes infections (cold sores, chickenpox, shingles, or genital herpes).

It is not known if VALTREX is safe and effective in people with weakened immune systems, other than for control of outbreaks of genital herpes in people with HIV-1.
It is not known if VALTREX is safe and effective in people 18 years of age and older with chickenpox.
It is not known if VALTREX is safe and effective in children:
- less than 12 years of age with cold sores
- less than 2 years of age with chickenpox
- less than 18 years of age with genital herpes or shingles

Before you take VALTREX, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems, including if you receive dialysis.
are pregnant or plan to become pregnant. It is not known if VALTREX will harm your unborn baby. You and your healthcare provider will decide if you will take VALTREX if you are pregnant.

How should I take VALTREX?

Tell your healthcare provider if your child cannot swallow VALTREX tablets. Your healthcare provider can prescribe VALTREX as an oral suspension for your child.
If you are taking VALTREX to treat outbreaks of cold sores, chickenpox, shingles, or genital herpes, take VALTREX as soon as you have the first symptoms of infection such as tingling, itching, or burning, or when the sore appears.
It is important for you to stay well hydrated during treatment with VALTREX. Be sure to drink plenty of fluids during this time.
If you miss a dose of VALTREX, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time or take more VALTREX than prescribed.

What are the possible side effects of VALTREX? VALTREX can cause serious side effects including:

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS). TTP and HUS have happened in people with weakened immune systems taking VALTREX and have led to death. TTP and HUS are disorders that can cause small blood clots to form throughout the body and decrease blood flow to body organs such as the brain, heart, and kidneys. Your healthcare provider will stop treatment with VALTREX if you have signs or symptoms of TTP and HUS.

Elderly people are more likely to get certain side effects. Talk to your healthcare provider if this is a concern for you.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.