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.

LINEZOLID IN SODIUM CHLORIDE 0.9% IN PLASTIC CONTAINER (NDA-206473)

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

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05/29/2025 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Rhabdomyolysis

New subsection added:

Rhabdomyolysis has been reported with the use of linezolid, including Linezolid injection [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine or elevated creatine phosphokinase are observed, discontinue Linezolid injection and initiate appropriate therapy.

6 Adverse Reactions

Addition of the following bulleted line listing:

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

Myelosuppression [see Warnings and Precautions (5.1)]
Peripheral and Optic Neuropathy [see Warnings and Precautions (5.2)]
Serotonin Syndrome [see Warnings and Precautions (5.3)]
Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.5)]
Lactic Acidosis [see Warnings and Precautions (5.7)]
Convulsions [see Warnings and Precautions (5.8)]
Rhabdomyolysis [see Warnings and Precautions (5.9)]
Hypoglycemia [see Warnings and Precautions (5.10)]
Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.11)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…

Rhabdomyolysis [see Warnings and Precautions (5.9)].
…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Rhabdomyolysis

Advise patients to inform their physician if they experience signs and symptoms of rhabdomyolysis including muscle pain, tenderness or weakness and dark urine [see Warnings and Precautions (5.9)].

…

11/08/2024 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelosuppression

Additions and/or revisions underlined:

…

Thrombocytopenia has been reported more often in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate to severe hepatic impairment. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those with severe renal impairment or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression [see Adverse Reactions (6.2)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia has been reported more often in patients with severe renal impairment and in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.1)]; sideroblastic anemia.

…

02/17/2022 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.10 Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Selection (SIADH)

Postmarketing cases of hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in patients treated with linezolid. In reported cases, the signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death. Monitor serum sodium levels regularly in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or SIADH while taking linezolid. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue linezolid, and institute appropriate supportive measures.

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information to bulleted line listing:

Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.10)].

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

PATIENT COUNSELING INFORMATION

Newly added information:

Hyponatremia and/or SIADH

Advise patients at risk for hyponatremia to inform their physician if they experience signs and symptoms of hyponatremia and/or SIADH, including confusion, somnolence, generalized weakness, and respiratory distress [see Warnings and Precautions (5.10)].

01/18/2022 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Serotonin Syndrome

Additions underlined

…

Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…

Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and linezolid [see Warnings and Precautions (5.3)].

…

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Serotonin Syndrome

Advise patients to inform their physician if taking serotonergic agents, including serotonin re-uptake inhibitors or other antidepressants and opioids [see Warnings and Precautions (5.3)].

…

07/29/2021 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…

Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.

…

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion

Risk Summary

Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.5 times (mice), equivalent to (rats), or 0.06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6.5 times the estimated human exposure. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs (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

Animal Data

In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6-16 (6.5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion. Neither maternal nor embryo-fetal toxicities were observed at doses up to

150 mg/kg/day. Fetal malformations were not observed.

In rats, fetal toxicity was observed at 15 and 50 mg/kg/day administered orally from GD 6-17 (exposures

0.22 times to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Fetal malformations were not observed. Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.

In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6-20 (0.06 times the estimated human exposure based on AUCs). Fetal malformations were not observed.

When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation (GD 6 through Lactation Day 20), survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

8.2 Lactation

PLLR conversion

Risk Summary

Linezolid is present in breast milk. Based on data from available published case reports, the daily dose of linezolid that the infant would receive from breastmilk would be approximately 6% to 9% of the recommended therapeutic infant dose (10 mg/kg every 8 hours). There is no information on the effects of linezolid on the breastfed infant; however, diarrhea and vomiting were the most common adverse reactions reported in clinical trials in infants receiving linezolid therapeutically [see Adverse Reactions

(6.1)] and (see Clinical Considerations). There is no information on the effects of linezolid on milk production.

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

Clinical Considerations

Advise lactating women to monitor a breastfed infant for diarrhea and vomiting.

8.3 Females and Males of Reproductive Potential

PLLR conversion

Infertility

Males

Based on findings from studies in rats, linezolid may reversibly impair fertility in male patients [see Nonclinical Toxicology (13.1)].

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Lactic Acidosis

Advise patients to inform their physician if they experience repeated episodes of nausea or vomiting while receiving linezolid [see Warnings and Precautions (5.7)].

…

Infertility

Advise male patients that linezolid injection may reversibly impair fertility [see Use in Specific Populations (8.3)].

08/22/2018 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia); sideroblastic anemia.
Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision.
Convulsions.
Anaphylaxis, angioedema, and bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome.

12/15/2017 (SUPPL-1)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Adults

The safety of linezolid formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. For all indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid.

(please refer to label to view Table 2)

…

Pediatric Patients

The safety of linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator- controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established.

For all indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.

(please refer to label to view Table 3)

…

For all indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients.

…

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Advise patients that:

Linezolid may be taken with or without food.
…