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.

AUGMENTIN ES-600 (NDA-050755)

(AMOXICILLIN; CLAVULANATE POTASSIUM)

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

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12/20/2024 (SUPPL-31)

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 up to approximately 2 times the amount of amoxicillin and 15 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of AUGMENTIN ES-600, 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 of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate. The amoxicillin doses in rodents (based on body surface area and assuming a 20 kg child) were approximately 2 times (rats) or equal to (mice) the recommended clinical AUGMENTIN ES-600 dose of 90/6.4 mg/kg/day. For clavulanate, these dose multiples were approximately 15 times and 7.5 times the recommended daily dose of AUGMENTIN ES-600.

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 ES-600 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 ES-600 and any potential adverse effects on the breastfed child from AUGMENTIN ES-600 or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

Acute Otitis Media

The safety and effectiveness of AUGMENTIN ES-600 have been established in pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg, for the treatment of acute otitis media, and the information on this use is discussed throughout the labeling.

The safety and effectiveness of AUGMENTIN ES-600 in pediatric patients younger than 3 months of age have not been established.

The safety and effectiveness of Augmentin ES-600 have not been established in pediatric patients aged 3 months to 12 years weighing more than 40 kg.

Acute Bacterial Sinusitis

The safety and effectiveness of AUGMENTIN ES-600 have been established for the treatment of pediatric patients (3 months to 12 years of age) with acute bacterial sinusitis. This use is supported by evidence from adequate and well-controlled studies of AUGMENTIN XRTM Extended Release Tablets in adults with acute bacterial sinusitis, studies of AUGMENTIN ES- 600 in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin and clavulanate in pediatric patients taking AUGMENTIN ES-600 [see Clinical Pharmacology (12)] and adults taking AUGMENTIN XR.

05/01/2024 (SUPPL-29)

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 the use of amoxicillin, a component of AUGMENTIN ES-600 [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 ES-600 and institute appropriate therapy.

6 Adverse Reactions

Additions and revisions underlined:

The following are discussed in more detail in other sections of the labeling [see Warnings and Precautions (5)]:

Anaphylactic reactions [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions (SCAR) [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)].

. . .

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

. . .

06/30/2022 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Allergic Reactions, including Anaphylaxis

Additions and/or revisions underlined:

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including AUGMENTIN ES-600. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with AUGMENTIN ES-600, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue AUGMENTIN ES-600 and institute appropriate therapy.

5.2 Severe Cutaneous Adverse Reactions

Newly added subsection

AUGMENTIN ES-600 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 ES- 600 discontinued if lesions progress.

5.8 Development of Drug-Resistant Bacteria

Additions and/or revisions underlined:

Prescribing AUGMENTIN ES-600 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 [see Warnings and Precautions (5)]:

· Anaphylactic reactions [see Warnings and Precautions (5.1)]

· Severe Cutaneous Adverse Reactions (SCAR) [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:

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of AUGMENTIN products, including AUGMENTIN ES- 600. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to AUGMENTIN.

Gastrointestinal: 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)].

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)].

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibacterials. Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with AUGMENTIN or AUGMENTIN ES-600. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see Contraindications (4.2), Warnings and Precautions (5.3)].

Renal: Interstitial nephritis and hematuria have been reported. Crystalluria has also been reported [see Overdosage (10)].

Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.

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

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

17 PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label