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.

HEPSERA (NDA-021449)

(ADEFOVIR DIPIVOXIL)

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

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12/28/2018 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Coadministration with Other Products

(Additions and/or revisions are underlined)

HEPSERA should not be used concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

7 Drug Interactions

7 DRUG INTERACTIONS

(Additions and/or revisions are underlined)

HEPSERA should not be administered in combination with products containing tenofovir disoproxil fumarate or tenofovir alafenamide

8 Use in Specific Populations

8.1 Pregnancy

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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to HEPSERA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258- 4263.

Risk Summary

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects, miscarriage or adverse maternal or fetal outcomes. Adefovir disoproxil (ADV) use during pregnancy has been evaluated in a limited number of individuals reported to the APR and the number of exposures to adefovir is insufficient to make a risk assessment compared to a reference population. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background rate of miscarriage in the U.S. general population is 15–20%.

In animal reproduction studies with oral ADV, no adverse developmental effects were observed at exposures (Cmax) 23 times higher in rats and 40 times higher in rabbits than those at the recommended human dose (RHD) of HEPSERA (see Data).

Data

Animal Data

In an embryo-fetal development study, ADV was administered orally to pregnant rabbits (at 1, 5, or 20 mg/kg/day) during organogenesis (on gestation day 6 through 18). No adverse developmental effects were observed at up to the highest dose tested, at systemic exposure (Cmax) 40 times that in humans at the RHD of HEPSERA.

In a pre/post-natal development study, ADV was administered orally to pregnant rats (at 2.5, 10, or 40 mg/kg/day) from organogenesis, through late gestation, delivery, and lactation (gestation day 7 to lactation/postpartum day 20). Reduced body weight of the offspring due to maternal toxicity was observed at systemic exposure 23 times that in humans at the RHD of HEPSERA.

In an embryo-fetal development study, ADV was administered intravenously to pregnant rats (at 2.5, 10, and 20 mg/kg/day) during organogenesis (gestation day 6 through 15). Embryo-fetal toxicity including malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) and skeletal variations (reduction of ossified metacarpal bones, increases in thoracic vertebrae and decreases in lumbar vertebrae) occurred at systemic exposure (Cmax) 38 times that in humans at the RHD of HEPSERA. No adverse developmental effects were observed at an exposure (Cmax) 12 times that in humans at the RHD of HEPSERA.

8.2 Lactation

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

Risk Summary

It is not known whether adefovir is present in human breast milk, affects human milk production, or has effects on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEPSERA and any potential adverse effects on the breastfed infant from HEPSERA or from the underlying maternal condition.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

Inform patients of the potential risks and benefits of HEPSERA and of alternative modes of therapy.

Instruct patients to:

-Follow a regular dosing schedule to avoid missing doses.

-Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.

-Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.

Advise patients that:

-The optimal duration of HEPSERA treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

-Patients should not discontinue HEPSERA without first informing their physician.

-Routine laboratory monitoring and follow-up with a physician is important during HEPSERA therapy.

-Obtaining HIV antibody testing prior to starting HEPSERA is important.

-HEPSERA should not be administered concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

-Lamivudine-resistant patients should use HEPSERA in combination with lamivudine and not as HEPSERA monotherapy.

-Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to HEPSERA.

Other

Patient Information

(Section format has been revised, please refer to label)