Linezolid

Warnings and Precautions, Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (5.10) 10/2021

1 INDICATIONS AND USAGE Linezolid for oral suspension 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) ; Uncomplicated skin and skin structure infections (1.4) ; Vancomycin-resistant Enterococcus faecium infections. (1.5) Limitations of Use (1.6) : Linezolid for oral suspension is not indicated for the treatment of Gram-negative infections. The safety and efficacy of Linezolid for oral suspension 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 for oral suspension formulations and other antibacterial drugs, linezolid should be used only treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.7) 1.1 Nosocomial Pneumonia Linezolid for oral suspension is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14) ]. 1.2 Community-acquired Pneumonia Linezolid for oral suspension 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) ]. 1.3 Complicated Skin and Skin Structure Infections Linezolid for oral suspension 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 for oral suspension has not been studied in the treatment of decubitus ulcers [see Clinical Studies (14) ]. 1.4 Uncomplicated Skin and Skin Structure Infections Linezolid for oral suspension is indicated for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [see Clinical Studies (14) ]. 1.5 Vancomycin-resistant Enterococcus faecium Infections Linezolid for oral suspension is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies (14) ]. 1.6 Limitations of Use Linezolid for oral suspension 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 for oral suspension formulations given for longer than 28 days have not been evaluated in controlled clinical trials [see Clinical Studies (14) ]. 1.7 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid for oral suspension and other antibacterial drugs, linezolid for oral suspension 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.

2 DOSAGE AND ADMINISTRATION Dosage, Route, and Frequency of Administration Infection Pediatric Patients (Birth through 11 years of Age) Adults and Adolescents (12 years and Older) Duration (days) Nosocomial pneumonia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral every 8 hours 5 to 11 yrs: 10 mg/kg oral every 12 hours Adults: 400 mg oral every 12 hours Adolescents: 600 mg oral every 12 hours 10 to 14 2.1 General Dosage and Administration The recommended dosage for linezolid formulations for the treatment of infections is described in Table 1. Table 1. Dosage Guidelines for Linezolid for Oral Suspension Infection * Dosage, Route and Frequency of Administration Recommended Duration of Treatment (consecutive days) Pediatric Patients † (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia 10 mg/kg intravenously or oral ‡ every 8 hours 600 mg intravenously or oral ‡ every 12 hours 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections , including concurrent bacteremia 10 mg/kg intravenously or oral ‡ every 8 hours 600 mg intravenously or oral ‡ every 12 hours 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral ‡ every 8 hours 5 to 11 yrs: 10 mg/kg oral ‡ every 12 hours Adults: 400 mg oral‡ every 12 hours Adolescents: 600 mg oral ‡ every 12 hours 10 to 14 * Due to the designated pathogens [ see Indications and Usage (1) ] † Neonates less than 7 days : Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [ see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ]. ‡ Oral dosing using either linezolid tablets or linezolid for oral suspension [ see How Supplied/Storage and Handling (16) ]. No dose adjustment is necessary when switching from intravenous to oral administration. 2.5 Constitution of Oral Suspension Linezolid for oral suspension is supplied as a powder/granule for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake . Store constituted suspension at room temperature. Use within 21 days after constitution.

3 DOSAGE FORMS AND STRENGTHS Linezolid for oral suspension: White or off white to brown granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL. • For oral suspension: 100 mg of linezolid per each 5 mL. ( 3 )

4 CONTRAINDICATIONS 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) 4.1 Hypersensitivity Linezolid for oral suspension formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. 4.2 Monoamine Oxidase Inhibitors 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.

6 ADVERSE REACTIONS Most common adverse reactions (>5% of adult and/or pediatric patients treated with linezolid for oral suspension) include: diarrhea, vomiting, headache, nausea, and anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-886-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. 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. Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of linezolid -treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other 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. Table 2. Incidence (%) of Treatment–Emergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg by mouth every 12 hours (n=548) Clarithromycin 250 mg by mouth every 12 hours (n=537) Linezolid 600 mg every 12 hours (n=1498) All Other Comparators Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. (n=1464) Headache 8.8 8.4 5.7 4.4 Diarrhea 8.2 6.1 8.3 6.4 Nausea 5.1 4.5 6.6 4.6 Vomiting 2 1.5 4.3 2.3 Dizziness 2.6 3 1.8 1.5 Rash 1.1 1.1 2.3 2.6 Anemia 0.4 0 2.1 1.4 Taste alteration 1.8 2 1 0.3 Vaginal moniliasis 1.8 1.3 1.1 0.5 Oral moniliasis 0.5 0 1.7 1 Abnormal liver function tests 0.4 0.2 1.6 0.8 Fungal infection 1.5 0.2 0.3 0.2 Tongue discoloration 1.3 0 0.3 0 Localized abdominal pain 1.3 0.6 1.2 0.8 Generalized abdominal pain 0.9 0.4 1.2 1 Of the patients treated for uSSSIs, 3.5% of linezolid -treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, 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. 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 % (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Of the pediatric patients treated for uSSSIs, 19.2% of linezolid-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event. For all other 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 incid …

7 DRUG INTERACTIONS Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. ( 4.2 , 5.3 , 5.6 , 7 , 12.3 ) 7.1 Monoamine Oxidase Inhibitors Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [ see Contraindications (4.2) and Clinical Pharmacology (12.3) ]. 7.2 Adrenergic and Serotonergic Agents Linezolid has the potential for interaction with adrenergic and serotonergic agents [ see Warnings and Precautions (5.3, 5.6 ) and Clinical Pharmacology (12.3) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 to 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 to 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 to 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 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 R …

12.1 Mechanism of Action Linezolid is an antibacterial drug [see Microbiology (12.4) ].

11 DESCRIPTION Linezolid for oral suspension contain linezolid USP, 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 C 16 H 20 FN 3 O 4 . Its molecular weight is 337.35, and its chemical structure is represented below: Linezolid for oral suspension is supplied as white or off white to brown granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are anhydrous citric acid powder, aspartame, carboxymethylcellulose sodium, colloidal silicon dioxide, glycyrrhizinate ammonium, hypromellose, mannitol, microcrystalline cellulose, sodium benzoate, sodium chloride, sucrose, trisodium citrate dihydrate, xanthan gum, and flavors [ see Patient Counseling Information (17) ]. The sodium (Na + ) content is 8.18 mg/5 mL. Linezolidstructure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.3 Oral Suspension Linezolid for oral suspension is available as a dry, white or off-white to brown granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL. Linezolid for oral suspension is supplied as follows: 100 mg/5 mL in 250 mL glass bottles NDC 31722-865-25 16.4 Storage and Handling Store at 25oC (77oF); excursions permitted to 15 to 30oC (59 to 86oF) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed to protect from moisture.