Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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.

AUGMENTIN XR (NDA-050785)

(AMOXICILLIN; CLAVULANATE POTASSIUM)

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

Download Data

Expand all

12/20/2024 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Skin Rash in Patients with Mononucleosis [see Warnings and Precautions (5.6)]

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use with amoxicillin and clavulanate during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates (see Data). Reproduction studies performed in pregnant rodents, given oral doses up to approximately 1.6 times the amount of amoxicillin and 13 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of AUGMENTIN XR, revealed no evidence of harm to the fetus (see Data).

The 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.

Data

Human Data

One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg amoxicillin and 125 mg clavulanic acid (amoxicillin and clavulanate, n=1,212), amoxicillin and clavulanate and erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or until delivery. Amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal necrotizing enterocolitis: 1.9% (n = 24) in the amoxicillin and clavulanate only group versus 0.5% (n = 6) in the placebo group (p = 0.001), and 1.8% (n = 44) in the any amoxicillin and clavulanate group versus 0.7% (n =17) in the no amoxicillin and clavulanate group (p = 0.0005).

Animal Data

Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate (2:1 ratio formulation) at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate. In terms of body surface area, the doses in rats were 1.6 times the Maximum Human Recommended Dose (MHRD) of amoxicillin and 13 times the MHRD for clavulanate in AUGMENTIN XR. For mice, these doses were 0.9 and 7.4 times the MHRD of amoxicillin and clavulanate, respectively.

8.2 Lactation

PLLR conversion:

Risk Summary

Data from a published clinical lactation study report that amoxicillin is present in human milk. There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and clavulanate through breast milk; therefore, infants exposed to AUGMENTIN XR should be monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AUGMENTIN XR and any potential adverse effects on the breastfed child from AUGMENTIN XR or from the underlying maternal condition.

05/01/2024 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Drug-Induced Enterocolitis Syndrome (DIES)

Newly added subsection:

Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of AUGMENTIN XR [see Adverse Reactions (6.2)], with most cases occurring in pediatric patients less than or equal to 18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue AUGMENTIN XR and institute appropriate therapy.

5.6 Skin Rash in Patients with Mononucleosis

Newly added subsection:

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, AUGMENTIN XR should not be administered to patients with mononucleosis.

6 Adverse Reactions

Additions and revisions underlined:

The following are discussed in more detail in other sections of the labeling:

Anaphylactic reactions [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3)]
Hepatic Dysfunction [see Warnings and Precautions (5.4)]

Clostridioides difficile-associated diarrhea (CDAD) [see Warnings and Precautions (5.5)]

6.2 Postmarketing Experience

Additions and revisions underlined:

. . .

Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.5)].

. . .

Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis.

. . .

11/02/2022 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Cutaneous Adverse Reactions

New subsection added

AUGMENTIN XR may cause severe cutaneous adverse reactions (SCAR), such as Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash, they should be monitored closely, and AUGMENTIN XR discontinued if lesions progress.

5.7 Development of Drug-Resistant Bacteria

Additions and/or revisions underlined

Prescribing AUGMENTIN XR in the absence of a proven or strongly suspected bacterial

infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 Adverse Reactions

Additions and/or revisions underlined:

The following are discussed in more detail in other sections of the labeling:

Anaphylactic reactions [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
Hepatic Dysfunction [see Warnings and Precautions (5.3)]
Clostridioides difficile-associated diarrhea (CDAD) [see Warnings and Precautions (5.4)]

6.2 Postmarketing Experience

Additions and/or revisions underlined

…

Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions (5.1)].

Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis [see Warnings and Precautions (5.2)].

…

Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, confusion, convulsions, dizziness, headache, insomnia, and reversible hyperactivity have been reported

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

Severe Cutaneous Adverse Reactions (SCAR)

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking AUGMENTIN XR immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions (5.2)].

…

Diarrhea

Counsel patients that diarrhea is a common problem caused by antibacterials drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial drug. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician as soon as possible.

…