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.

VANCOMYCIN HYDROCHLORIDE (NDA-211962)

(VANCOMYCIN HYDROCHLORIDE)

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

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05/28/2021 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Potential Risk of Exposure to Excipients During Early Pregnancy

(Additions and/or revisions underlined)

If use of vancomycin is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin. This formulation of Vancomycin Injection contains the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA). In a rabbit reproduction study, fetal spinal malformations occurred when the excipient PEG 400 was administered at dose exposures approximately 8 times the exposure at the maximum daily human dose. In a separate rabbit reproduction study, fetal spinal and cardiovascular malformations occurred when the excipient NADA was administered at dose exposures approximately 32 times the exposure at the maximum daily human dose. The active ingredient vancomycin is not known to be associated with embryo- fetal toxicity [see Use in Specific Populations (8.1)].

5.5 Severe Dermatologic Reactions

(Newly Added Subsection)

Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin. Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters.

Discontinue Vancomycin Injection at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling:

Infusion Reactions [see Warnings and Precautions (5.2)]
Nephrotoxicity [see Warnings and Precautions (5.3)]
Ototoxicity [see Warnings and Precautions (5.4)]

Severe Dermatologic Reactions [see Warnings and Precautions (5.5)]

Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.6)]
Hemorrhagic Occlusive Retinal Vasculitis [see Warnings and Precautions (5.7)]
Neutropenia [see Warnings and Precautions (5.8)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postmarketing use of vancomycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.5)].

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

This formulation of Vancomycin Injection is not recommended for use during the first or second trimester of pregnancy because it contains the excipients, PEG 400 and NADA, which caused fetal malformations in animal reproduction studies (see Data). Advise pregnant women of the potential risk to the fetus. If therapy with Vancomycin Injection is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin, free of PEG 400 and NADA.

The available data on use of this formulation of Vancomycin Injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available published data on vancomycin (without the excipients PEG 400 and NADA) use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes (see Data). There are no available data on first trimester use of vancomycin in pregnant women to assess the risk of major birth defects or miscarriage. Vancomycin alone did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose based on body surface area (see Data).

Reproduction studies in rabbits with intravenous doses of PEG 400 at approximately 8 times the maximum daily human dose based on systemic exposures of PEG 400 during organogenesis resulted in fetal spinal malformations. Reproduction studies in rabbits and rats using intravenous doses of NADA at approximately 32 and 20 times the maximum daily human dose, respectively, based on systemic exposures of NADA resulted in maternal toxicity and fetal spinal and cardiovascular malformations in rabbits, and maternal toxicity with no adverse embryo-fetal effects in rats…

Data

Human Data

Available data from postmarketing cases on use of this formulation of vancomycin injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug- associated risk of major birth defects, miscarriage, or other adverse maternal or infant outcomes.

There are no available data on first trimester use of vancomycin (without the excipients PEG 400 and NADA); however, available published data on use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes.

Animal Data

Animal reproduction studies conducted in rabbits administered intravenous PEG 400 at 2000 mg/kg (approximately 8 times the maximum daily human dose, based on AUC levels of PEG 400) during organogenesis (gestation days 6 to 19) resulted in fetal scoliosis (thoracic and lumbar) and increased incidence of delayed or incomplete ossification of the pubes, epiphyses, and talus bones. No maternal toxicity was observed up to the maximum dose tested.

Similarly, in animal reproduction studies conducted in pregnant rabbits (gestation days 6 to 19) and pregnant rats (gestation days 6 to 17) administered intravenous NADA at 1680 and 3780 mg/kg, respectively (at 32 times or greater based on AUC levels of NADA) resulted in fetal scoliosis and a spectrum of cardiovascular anomalies in rabbits and no adverse effects on fetuses in rats. Increased incidence of delayed or incomplete ossifications of the metacarpals/metatarsals/phalanges and increased ossification (fused jugal/maxilla bones) were observed in rabbits at 1680 mg/kg. Minor non adverse fetal skeletal abnormalities were observed in rats at 3780 mg/kg which was also associated with maternal toxicity including increased incidence of litter loss [see Clinical Pharmacology (12.3)]..

No animal studies have been conducted to evaluate the potential reproductive and embryo-fetal effects of Vancomycin Injection (with the excipients PEG 400 and NADA).

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Potential Risk of Exposure to Excipients During Early Pregnancy

Advise patients to notify their healthcare provider if they are pregnant prior to treatment with this formulation of vancomycin [see Boxed Warning, Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Severe Dermatologic Reactions

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop Vancomycin Injection immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions or blisters to their healthcare provider [see Warnings and Precautions (5.5)].

01/29/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Severe Dermatologic Reactions

(Newly added information)

Discontinue Vancomycin Injection at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

6 Adverse Reactions

6.2 Post Marketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post marketing use of vancomycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.5)].

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

Patient Counseling Information

(Newly added information)

Severe Dermatologic Reactions