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.

ZOLEDRONIC ACID (NDA-204016)

(ZOLEDRONIC ACID)

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

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12/19/2018 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on area under the curve (AUC). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bissphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Osteonecrosis of the Jaw

Cases of osteonecrosis (primarily involving the jaw but also of other anatomical sites including hip, femur and external auditory canal) have been reported….

Hypersensitivity Reactions

CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; uveitis; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria; acquired Fanconi syndrome;..

8 Use in Specific Populations

8.1 Pregnancy

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

Risk Summary

Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on AUC.

Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix and are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal Data

8.2 Lactation

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

Risk Summary

After administration of Zoledronic Acid Injection, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production, or the breastfed child. Zoledronic acid binds to bone long term and may be released over weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after Zoledronic Acid Injection treatment.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiation of Zoledronic Acid Injection.

Contraception

Females

Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. Zoledronic acid binds to bone long term and may be released over weeks to years. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.

Infertility

Females

Based on animal studies, Zoledronic Acid Injection may impair fertility in females of reproductive potential.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Zoledronic Acid Injection is not indicated for use in pediatric patients.

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

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)