These Highlights Do Not Include All The Information Needed To Use Linezolid Injection Safely And Effectively. See Full Prescribing Information For Linezolid Injection.

Adults

The safety of linezolid formulations was evaluated in 2,046 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.

Discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.

Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light. It is recommended that the containers be kept in the overwrap until ready to use. Protect containers from freezing.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3,000 mg/kg/day and 2,000 mg/kg/day, respectively.

Linezolid injection contains linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide.

The empirical formula is C₁₆H₂₀FN₃O₄. Its molecular weight is 337.35, and its chemical structure is represented below:

Linezolid injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each container contains 600 mg of linezolid in 300 mL of a clear, colorless to slightly yellow aqueous solution. Inactive ingredients include: citric acid anhydrous USP 1.92 mg/mL, sodium chloride USP 9 mg/mL, sodium hydroxide NF 0.76 mg/mL, and water for injection USP. Sodium hydroxide NF and/or hydrochloric acid NF are used to adjust the pH. The sodium (Na⁺) content is 3.98 mg/mL (52 mEq/300 mL container).

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) ].

Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.

If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) and Clinical Studies (14) ]:

• •
  nosocomial pneumonia
• •
  complicated skin and skin structure infections
• •
  community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
• •
  vancomycin-resistant Enterococcus faecium infections

Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof.

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age <34 weeks) neonates <7 days of age, linezolid clearance is often lower than in full-term neonates <7 days of age. Consequently, preterm neonates <7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ].

In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12.3) and Dosage and Administration (2) ].

Of the 2,046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

• •
  Known hypersensitivity to linezolid or any of the other product components. (4.1)
• •
  Patients taking any monoamine oxidase inhibitors (MAOI) or within two weeks of taking an MAOI. (4.2)

Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid injection should receive immediate medical evaluation.

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) ]

Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. (4.2, 5.3, 5.6, 7, 12.3)

Linezolid injection is contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. 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) ].

In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1,200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1,200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.

Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)

Physical incompatibilities resulted when Linezolid injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Linezolid injection was combined with ceftriaxone sodium.

• •
  Linezolid injection is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Warnings and Precautions (5.4) ].
• •
  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials [see Clinical Studies (14) ].

Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.

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) ].

In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms).

Linezolid injection is an oxazolidinone-class antibacterial indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia (1.1); Community-acquired pneumonia (1.2); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis (1.3); Vancomycin-resistant Enterococcus faecium infections. (1.4)



Limitations of Use: (1.5)

• •
  Linezolid injection is not indicated for the treatment of Gram-negative infections.
• •
  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection formulations and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6)

Linezolid injection is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14) ].

Linezolid is an antibacterial drug [see Microbiology (12.4) ].

• •
  Myelosuppression: Monitor complete blood counts weekly. Thrombocytopenia has been reported more often in patients with severe renal and in patients with moderate to severe hepatic impairment. Consider discontinuation in patients who develop or have worsening myelosuppression. (5.1)
• •
  Peripheral and Optic Neuropathy: Reported primarily in patients treated for longer than 28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended. (5.2)
• •
  Serotonin Syndrome: Monitor patients taking serotonergic agents, including antidepressants and opioids, for signs of serotonin syndrome. Patients taking serotonergic antidepressants should receive Linezolid injection only if no other therapies are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation. (5.3)
• •
  A mortality imbalance was seen in an investigational study in linezolid-treated patients with catheter-related bloodstream infections. (5.4)
• •
  Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.5)
• •
  Potential interactions producing elevation of blood pressure: monitor blood pressure. (5.6)
• •
  Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Linezolid injection and initiate appropriate therapy. (5.9)
• •
  Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. (5.10)
• •
  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Monitor serum sodium levels regularly in patients at risk of hyponatremia and/or SIADH. (5.11)

• •
  Pediatric Patients-The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof. (2.1)

Linezolid injection: 600 mg/300 mL (2 mg/mL) linezolid in single-dose, ready-to-use flexible plastic container in a foil laminate overwrap.

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

• •
  Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.
• •
  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.
• •
  Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [see Warnings and Precautions (5.2) ].
• •
  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) ].
• •
  Lactic acidosis [see Warnings and Precautions (5.7) ]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.
• •
  Convulsions [see Warnings and Precautions (5.8) ].
• •
  Rhabdomyolysis [see Warnings and Precautions (5.9) ].
• •
  Hypoglycemia, including symptomatic episodes [see Warnings and Precautions (5.10) ].
• •
  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.11) ].
• •
  Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.

Clostridioides difficile-Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Linezolid injection is supplied in single-dose, ready-to-use container [see How Supplied/Storage and Handling (16) ]. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the containers in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous container in series connections. Additives should not be introduced into this solution. If Linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. Discard unused portion.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Linezolid injection with an infusion solution compatible with Linezolid injection and with any other drug(s) administered via this common line.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Linezolid injection is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see Clinical Studies (14) ].

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [see Contraindications (4.2) and Clinical Pharmacology (12.3) ].

Peripheral and optic neuropathies have been reported in patients treated with linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children.

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Linezolid injection for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Linezolid injection. If peripheral or optic neuropathy occurs, the continued use of Linezolid injection in these patients should be weighed against the potential risks.

Linezolid injection is available in a single-dose, ready-to-use flexible plastic container in a foil laminate overwrap. The container is available in the following package size:

The recommended dosage for Linezolid injection for the treatment of infections is described in Table 1. No dose adjustment is necessary when switching from intravenous to oral administration.

The maximum dose for pediatric patients should not exceed the recommended adult dose. The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof.

Linezolid has the potential for interaction with adrenergic and serotonergic agents [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3) ].

Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.

In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.

These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

Prescribing Linezolid injection 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.

Linezolid injection is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies (14) ].

Linezolid injection is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid injection has not been studied in the treatment of decubitus ulcers [see Clinical Studies (14) ].

300 mL

NDC 0409-4883-03

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

Each mL contains Linezolid 2 mg; Citric Acid anhydrous, USP,

1.92 mg; Sodium Hydroxide, 0.76 mg; Sodium Chloride, USP 9 mg in

Water for Injection. Adjust pH to 4.4 - 5.2 with Sodium Hydroxide

and/or Hydrochloric Acid.

Sterile and non-pyrogenic. Single-dose container. Recommended Dosage:

See Prescribing Information. Store at 20 to 25°C (68 to 77°F). Excursions

permitted to 15 to 30°C (59 to 86°F). [See USP Controlled Room

Temperature.] Protect from freezing. Linezolid is sensitive to light.

Use only if solution is clear and container is undamaged. Must

not be used in series connections. Do not remove caps until

ready for use. If leaks are found, discard solution as sterility

may be impaired.

Rx ONLY

Hospira

Distributed by Hospira, Inc.

lake Forest, IL 60045 USA

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.

Linezolid did not affect the fertility or reproductive performance of adult female rats given oral doses of up to 100 mg/kg/day for 14 days prior to mating through Gestation Day 7. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.

In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7 times greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.

300 mL

NDC 0409-4883-03

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL (2 mg/mL)

For Intravenous Infusion. Single-dose container

TO OPEN — TEAR AT NOTCH

Each mL contains Linezolid, 2 mg; Citric Acid anhydrous, USP, 1.92 mg;

Sodium Hydroxide, 0.76 mg; Sodium Chloride, USP 9 mg in Water for

Injection. pH adjusted to 4.4 - 5.2 with Sodium Hydroxide and/or

Hydrochloric Acid.

Discard unused portion. Recommended Dosage: See Prescribing

Information.

The overwrap is a moisture barrier. Do not remove unit from overwrap

until ready for use. Visually inspect overwrap for tears or holes. Discard

unit if overwrap is damaged or if solution is discolored in any way. Use

unit promptly when overwrap is opened.

Store at 20 to 25ºC (68 to 77ºF). Excursions permitted to 15 to 30ºC

(59 to 86ºF). [See USP Controlled Room Temperature.] Do not freeze.

Rx only

Linezolid is sensitive to light. After removing the overwrap,

check bag for minute leaks by squeezing container firmly.

If leaks are found, discard solution as sterility may be impaired.

MADE IN SINGAPORE

Distributed by Hospira Inc., Lake Forest, IL 60045 USA

Hospira

300 mL

NDC 0409-4883-11

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

EACH ML CONTAINS LINEZOLID,

2 MG; CITRIC ACID ANHYDROUS, USP,

1.92 MG; SODIUM HYDROXIDE, 0.76 MG;

SODIUM CHLORIDE, USP 9 MG IN WATER

FOR INJECTION. ADJUST pH TO 4.4 -

5.2 WITH SODIUM HYDROXIDE AND/OR

HYDROCHLORIC ACID.

STERILE AND NON-PYROGENIC. SINGLE-

DOSE CONTAINER. DOSAGE AND USE:

SEE INSERT. STORE AT 20 TO 25°C

(68 TO 77°F). EXCURSIONS PERMITTED

TO 15 TO 30°C (59 TO 86°F). [SEE USP

CONTROLLED ROOM TEMPERATURE.]

PROTECT FROM FREEZING. LINEZOLID

IS SENSITIVE TO LIGHT. RETAIN

IN OVERWRAP PRIOR TO USE. USE

ONLY IF SOLUTION IS CLEAR AND

CONTAINER IS UNDAMAGED. MUST

NOT BE USED IN SERIES CONNECTIONS.

VisIV IS A TRADEMARK OF HOSPIRA. DO

NOT REMOVE CAPS UNTIL READY FOR

USE. IF LEAKS ARE FOUND, DISCARD

SOLUTION AS STERILITY MAY BE

IMPAIRED.

VisIV™ Container

Rx ONLY

5

PP

IM-5097

HOSPIRA, INC.,

LAKE FOREST, IL 60045 USA

Hospira

SET

Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [see Drug Interactions (7) and Clinical Pharmacology (12.3) ].

300 mL

NDC 0409-4883-11

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

Single-dose container

F WR-1532

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

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 injection. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue Linezolid injection, and institute appropriate supportive measures.

An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.

Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Indications and Usage (1) ].

Adults

The safety of linezolid formulations was evaluated in 2,046 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.

Discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.

Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light. It is recommended that the containers be kept in the overwrap until ready to use. Protect containers from freezing.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3,000 mg/kg/day and 2,000 mg/kg/day, respectively.

Linezolid injection contains linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide.

The empirical formula is C₁₆H₂₀FN₃O₄. Its molecular weight is 337.35, and its chemical structure is represented below:

Linezolid injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each container contains 600 mg of linezolid in 300 mL of a clear, colorless to slightly yellow aqueous solution. Inactive ingredients include: citric acid anhydrous USP 1.92 mg/mL, sodium chloride USP 9 mg/mL, sodium hydroxide NF 0.76 mg/mL, and water for injection USP. Sodium hydroxide NF and/or hydrochloric acid NF are used to adjust the pH. The sodium (Na⁺) content is 3.98 mg/mL (52 mEq/300 mL container).

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) ].

Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.

If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) and Clinical Studies (14) ]:

• •
  nosocomial pneumonia
• •
  complicated skin and skin structure infections
• •
  community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
• •
  vancomycin-resistant Enterococcus faecium infections

Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof.

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age <34 weeks) neonates <7 days of age, linezolid clearance is often lower than in full-term neonates <7 days of age. Consequently, preterm neonates <7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ].

In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12.3) and Dosage and Administration (2) ].

Of the 2,046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

• •
  Known hypersensitivity to linezolid or any of the other product components. (4.1)
• •
  Patients taking any monoamine oxidase inhibitors (MAOI) or within two weeks of taking an MAOI. (4.2)

Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid injection should receive immediate medical evaluation.

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) ]

Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. (4.2, 5.3, 5.6, 7, 12.3)

Linezolid injection is contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. 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) ].

In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1,200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1,200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.

Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)

Physical incompatibilities resulted when Linezolid injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Linezolid injection was combined with ceftriaxone sodium.

• •
  Linezolid injection is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Warnings and Precautions (5.4) ].
• •
  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials [see Clinical Studies (14) ].

Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.

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) ].

In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms).

Linezolid injection is an oxazolidinone-class antibacterial indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia (1.1); Community-acquired pneumonia (1.2); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis (1.3); Vancomycin-resistant Enterococcus faecium infections. (1.4)



Limitations of Use: (1.5)

• •
  Linezolid injection is not indicated for the treatment of Gram-negative infections.
• •
  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection formulations and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6)

Linezolid injection is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14) ].

Linezolid is an antibacterial drug [see Microbiology (12.4) ].

• •
  Myelosuppression: Monitor complete blood counts weekly. Thrombocytopenia has been reported more often in patients with severe renal and in patients with moderate to severe hepatic impairment. Consider discontinuation in patients who develop or have worsening myelosuppression. (5.1)
• •
  Peripheral and Optic Neuropathy: Reported primarily in patients treated for longer than 28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended. (5.2)
• •
  Serotonin Syndrome: Monitor patients taking serotonergic agents, including antidepressants and opioids, for signs of serotonin syndrome. Patients taking serotonergic antidepressants should receive Linezolid injection only if no other therapies are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation. (5.3)
• •
  A mortality imbalance was seen in an investigational study in linezolid-treated patients with catheter-related bloodstream infections. (5.4)
• •
  Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.5)
• •
  Potential interactions producing elevation of blood pressure: monitor blood pressure. (5.6)
• •
  Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Linezolid injection and initiate appropriate therapy. (5.9)
• •
  Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. (5.10)
• •
  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Monitor serum sodium levels regularly in patients at risk of hyponatremia and/or SIADH. (5.11)

• •
  Pediatric Patients-The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof. (2.1)

Linezolid injection: 600 mg/300 mL (2 mg/mL) linezolid in single-dose, ready-to-use flexible plastic container in a foil laminate overwrap.

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

• •
  Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.
• •
  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.
• •
  Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [see Warnings and Precautions (5.2) ].
• •
  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) ].
• •
  Lactic acidosis [see Warnings and Precautions (5.7) ]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.
• •
  Convulsions [see Warnings and Precautions (5.8) ].
• •
  Rhabdomyolysis [see Warnings and Precautions (5.9) ].
• •
  Hypoglycemia, including symptomatic episodes [see Warnings and Precautions (5.10) ].
• •
  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.11) ].
• •
  Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.

Clostridioides difficile-Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Linezolid injection is supplied in single-dose, ready-to-use container [see How Supplied/Storage and Handling (16) ]. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the containers in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous container in series connections. Additives should not be introduced into this solution. If Linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. Discard unused portion.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Linezolid injection with an infusion solution compatible with Linezolid injection and with any other drug(s) administered via this common line.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Linezolid injection is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see Clinical Studies (14) ].

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [see Contraindications (4.2) and Clinical Pharmacology (12.3) ].

Peripheral and optic neuropathies have been reported in patients treated with linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children.

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Linezolid injection for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Linezolid injection. If peripheral or optic neuropathy occurs, the continued use of Linezolid injection in these patients should be weighed against the potential risks.

Linezolid injection is available in a single-dose, ready-to-use flexible plastic container in a foil laminate overwrap. The container is available in the following package size:

The recommended dosage for Linezolid injection for the treatment of infections is described in Table 1. No dose adjustment is necessary when switching from intravenous to oral administration.

The maximum dose for pediatric patients should not exceed the recommended adult dose. The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof.

Linezolid has the potential for interaction with adrenergic and serotonergic agents [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3) ].

Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.

In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.

These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

Prescribing Linezolid injection 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.

Linezolid injection is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies (14) ].

Linezolid injection is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid injection has not been studied in the treatment of decubitus ulcers [see Clinical Studies (14) ].

300 mL

NDC 0409-4883-03

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

Each mL contains Linezolid 2 mg; Citric Acid anhydrous, USP,

1.92 mg; Sodium Hydroxide, 0.76 mg; Sodium Chloride, USP 9 mg in

Water for Injection. Adjust pH to 4.4 - 5.2 with Sodium Hydroxide

and/or Hydrochloric Acid.

Sterile and non-pyrogenic. Single-dose container. Recommended Dosage:

See Prescribing Information. Store at 20 to 25°C (68 to 77°F). Excursions

permitted to 15 to 30°C (59 to 86°F). [See USP Controlled Room

Temperature.] Protect from freezing. Linezolid is sensitive to light.

Use only if solution is clear and container is undamaged. Must

not be used in series connections. Do not remove caps until

ready for use. If leaks are found, discard solution as sterility

may be impaired.

Rx ONLY

Hospira

Distributed by Hospira, Inc.

lake Forest, IL 60045 USA

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.

Linezolid did not affect the fertility or reproductive performance of adult female rats given oral doses of up to 100 mg/kg/day for 14 days prior to mating through Gestation Day 7. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.

In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7 times greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.

300 mL

NDC 0409-4883-03

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL (2 mg/mL)

For Intravenous Infusion. Single-dose container

TO OPEN — TEAR AT NOTCH

Each mL contains Linezolid, 2 mg; Citric Acid anhydrous, USP, 1.92 mg;

Sodium Hydroxide, 0.76 mg; Sodium Chloride, USP 9 mg in Water for

Injection. pH adjusted to 4.4 - 5.2 with Sodium Hydroxide and/or

Hydrochloric Acid.

Discard unused portion. Recommended Dosage: See Prescribing

Information.

The overwrap is a moisture barrier. Do not remove unit from overwrap

until ready for use. Visually inspect overwrap for tears or holes. Discard

unit if overwrap is damaged or if solution is discolored in any way. Use

unit promptly when overwrap is opened.

Store at 20 to 25ºC (68 to 77ºF). Excursions permitted to 15 to 30ºC

(59 to 86ºF). [See USP Controlled Room Temperature.] Do not freeze.

Rx only

Linezolid is sensitive to light. After removing the overwrap,

check bag for minute leaks by squeezing container firmly.

If leaks are found, discard solution as sterility may be impaired.

MADE IN SINGAPORE

Distributed by Hospira Inc., Lake Forest, IL 60045 USA

Hospira

300 mL

NDC 0409-4883-11

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

EACH ML CONTAINS LINEZOLID,

2 MG; CITRIC ACID ANHYDROUS, USP,

1.92 MG; SODIUM HYDROXIDE, 0.76 MG;

SODIUM CHLORIDE, USP 9 MG IN WATER

FOR INJECTION. ADJUST pH TO 4.4 -

5.2 WITH SODIUM HYDROXIDE AND/OR

HYDROCHLORIC ACID.

STERILE AND NON-PYROGENIC. SINGLE-

DOSE CONTAINER. DOSAGE AND USE:

SEE INSERT. STORE AT 20 TO 25°C

(68 TO 77°F). EXCURSIONS PERMITTED

TO 15 TO 30°C (59 TO 86°F). [SEE USP

CONTROLLED ROOM TEMPERATURE.]

PROTECT FROM FREEZING. LINEZOLID

IS SENSITIVE TO LIGHT. RETAIN

IN OVERWRAP PRIOR TO USE. USE

ONLY IF SOLUTION IS CLEAR AND

CONTAINER IS UNDAMAGED. MUST

NOT BE USED IN SERIES CONNECTIONS.

VisIV IS A TRADEMARK OF HOSPIRA. DO

NOT REMOVE CAPS UNTIL READY FOR

USE. IF LEAKS ARE FOUND, DISCARD

SOLUTION AS STERILITY MAY BE

IMPAIRED.

VisIV™ Container

Rx ONLY

5

PP

IM-5097

HOSPIRA, INC.,

LAKE FOREST, IL 60045 USA

Hospira

SET

Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [see Drug Interactions (7) and Clinical Pharmacology (12.3) ].

300 mL

NDC 0409-4883-11

Linezolid Injection

in 0.9% Sodium Chloride

600 mg/300 mL

(2 mg/mL)

For Intravenous Infusion

Single-dose container

F WR-1532

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

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 injection. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue Linezolid injection, and institute appropriate supportive measures.

An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.

Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Indications and Usage (1) ].