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.

FAMVIR (NDA-020363)

(FAMCICLOVIR)

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

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12/18/2018 (SUPPL-50)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Pregnancy and Lactation Labeling Rule (PLLR); additions and/or revisions are underlined

Risk Summary

Available data from pharmacovigilance reports with FAMVIR use in pregnant women have not identified a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the fetus associated with untreated herpes simplex virus during pregnancy. After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). In animal reproduction studies with famciclovir, no evidence of adverse developmental outcomes was observed at systemic exposures of penciclovir (AUC) slightly higher than those at the maximum recommended human dose (MRHD) of FAMVIR.

The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15- 20%, respectively.

Novartis Pharmaceuticals Corporation maintains a pregnancy reporting system to monitor maternal-fetal outcomes of pregnant women exposed to FAMVIR. Healthcare providers are encouraged to report pregnancies and pregnancy outcomes to the Novartis Adverse Event reporting line at 1-888-NOW-NOVA (669-6682).

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

The risk of neonatal herpes infection varies from 30% to 50% for genital herpes simplex virus (HSV) infections that occur in late pregnancy (third trimester), whereas in early pregnancy, infection carries a risk of about 1%. A primary herpes outbreak 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

Animal Data

Famciclovir was administered orally to pregnant rats and rabbits (up to 1000 mg/kg/day) on gestation Day(s) 6 to 15, and to rats on gestation Day 15 to lactation/post-partum Day 25. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures of penciclovir (active metabolite) were 3.4 times (rats) and 1.6 times (rabbits) the human systemic exposure of penciclovir based on AUC at the MRHD.

8.2 Lactation

Pregnancy and Lactation Labeling Rule (PLLR); additions and/or revisions are underlined

Risk Summary

There are no data on the presence of famciclovir (prodrug) or penciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. Animal data indicate that penciclovir is present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FAMVIR and any potential adverse effects on the breastfed infant from FAMVIR or from the underlying maternal condition.

Data

Penciclovir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 40 mg per kg on lactation Day 12, with milk concentrations of up to approximately 8 times that of maternal plasma concentrations observed 0.5 hours postdose.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions are underlined

Infertility

Decreased fertility, due to testicular toxicity, was observed in male animals following repeated administration of famciclovir or penciclovir.

In two placebo-controlled studies, 130 men with a history of recurrent genital herpes received either oral FAMVIR (250 mg twice daily; n=66) or placebo (n=64) therapy for 18 weeks. The men were otherwise healthy and had a normal sperm profile prior to treatment. There was no evidence of significant effects on sperm count, motility or morphology during FAMVIR treatment or during an 8-week follow-up.

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

Patient Information

Extensive changes; please refer to labeling

09/16/2016 (SUPPL-47)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience (updated)

Immune system disorders: Anaphylactic shock, anaphylactic reaction (added)

Nervous system disorders: Dizziness, somnolence, seizure (added)

Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g., face, eyelid, periorbital, and pharyngeal edema), leukocytoclastic vasculitis (changed to hypersensitivity vasculitis)

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

See FDA-Approved Patient Labeling (changed to) Advise the patient to read the FDA-approved patient labeling.