Linezolid for Skin Infections

INDICATIONS AND USAGE Linezolid injection is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. 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 ) ]. 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 ( 1.1 ); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis ( 1.2 ); Uncomplicated skin and skin structure infections ( 1.2 ); Vancomycin-resistant Enterococcus faecium infections. ( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid 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. ( 1.4 ) 1.1 Pneumonia Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [ see Clinical Studies ( 14 ) ]. Community-acquired pneumonia caused by Streptococcus pneumoniae , including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [ see Clinical Studies ( 14 ) ]. 1.2 Skin and Skin Structure Infections 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 ) ]. Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [ see Clinical Studies ( 14 ) ]. 1.3 Vancomycin-resistant Enterococcus faecium Infections Vancomycin-resistant Enterococcus faecium infections , including cases with concurrent bacteremia [ see Clinical Studies ( 14 ) ]. 1.4 Usage 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. The safety and efficacy of linezolid injection given for longer than 28 days have not been evaluated in controlled clinical trials. 1.1 Pneumonia Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [ see Clinical Studies ( 14 ) ]. Community-acquired pneumonia caused by Streptococcus pneumoniae , including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [ see Clinical Studies ( 14 ) ]. 1.2 Skin and Skin Structure Infections 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 ) ]. Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [ see Clinical Studies ( 14 ) ]. 1.3 Vancomycin-resistant Enterococcus faecium Infections Vancomycin-resistant Enterococcus faecium infections , including cases with concurrent bacteremia [ see Clinical Studies ( 14 ) ]. 1.4 Usage 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. The safety and efficacy of linezolid injection given for longer than 28 days have not been evaluated in controlled clinical trials.

DOSAGE AND ADMINISTRATION Dosage, Route, and Frequency of Administration Infection Pediatric Patients Adults and Adolescents 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 Infection* Dosage and Route 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. No dose adjustment is necessary when switching from intravenous to oral administration. 2.2 Intravenous Administration Linezolid injection is supplied in single-use, ready-to-use flexible plastic containers. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for leakage by squeezing container firmly. If any leakage, discard solution as sterility may be impaired . Keep the infusion bag 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 flexible plastic 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. 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. 2.3 Compatibilities Compatible intravenous solutions include 0.9% Sodium Chloride Injection, 5% Dextrose Injection, and Lactated Ringer’s Injection. 2.4 Incompatibilities 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. 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 Infection* Dosage and Route 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. No dose adjustment is necessary when switching from intravenous to oral administration. 2.2 Intravenous Administration Linezolid injection is supplied in single-use, ready-to-use flexible plastic containers. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for leakage by squeezing container firmly. If any leakage, discard solution as sterility may be impaired . Keep the infusion bag 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 flexible plastic 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. 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. 2.3 Compatibilities Compatible intravenous solutions include 0.9% Sodium Chloride Injection, 5% Dextrose Injection, and Lactated Ringer’s Injection. 2.4 Incompatibilities 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 la

WARNINGS AND PRECAUTIONS • 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 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 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 ) • Phenylketonuria: Linezolid for Oral Suspension contains phenylalanine which can be harmful to patients with phenylketonuria. ( 5.12 ) 5.1 Myelosuppression 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 )]. 5.2 Peripheral and Optic Neuropathy 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 for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks. 5.3 Serotonin Syndrome 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). 5.4 Mortality Imbalance in an Investigational Study in Patients with Catheter-Related Bloodstream Infections, Including Those with Catheter-site Infections 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%); odds ratio 1.426, 95% CI 0.97, 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 )]. 5.5 Clostridioides difficile- Associated Diarrhea Clostridioides difficile-A ssociated 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 an

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) ]. Drug Interactions Drugs Metabolized by Cytochrome P450 Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen. Antibacterial Drugs Aztreonam : The pharmacokinetics of linezolid or aztreonam are not altered when administered together. Gentamicin : The pharmacokinetics of linezolid or gentamicin are not altered when administered together. Antioxidants The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2–9, subjects were given either Vitamin C (1,000 mg/day) or Vitamin E (800 IU/ day). The AUC 0–∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E. Strong CYP 3A4 Inducers Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid C max [90% CI, 15% – 27%] and a 32% decrease in linezolid AUC 0–12 [90% CI, 27% – 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure. Monoamine Oxidase Inhibition Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents. Adrenergic Agents Some individuals receiving linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response. Tyramine: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content [ see Patient Counseling Information (17) ]. Pseudoephedrine HCl or phenylpropanolamine HCl: A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects [ see Warnings and Precautions (5.6) and Drug Interactions (7) ]. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20–52 mm Hg) and 38 mm Hg (range: 18–79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively. Serotonergic Agents Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

ADVERSE REACTIONS Most common adverse reactions (>5% of adult and/or pediatric patients treated with linezolid) include: diarrhea, vomiting, headache, nausea, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ()] Peripheral and Optic Neuropathy [see Warnings and Precautions ()] Serotonin Syndrome [see Warnings and Precautions ()] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ()] Lactic Acidosis [see Warnings and Precautions ()] Convulsions [see Warnings and Precautions ()] Rhabdomyolysis [see Warnings and Precautions ()] Hypoglycemia [see Warnings and Precautions ()] Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions ()] 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 Uncomplicated Skin and Skin Structure Infections All Other Indications ADVERSE REACTIONS 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 2.0 1.5 4.3 2.3 Dizziness 2.6 3.0 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 2.0 1.0 0.3 Vaginal moniliasis 1.8 1.3 1.1 0.5 Oral moniliasis 0.5 0 1.7 1.0 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 1.0 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% (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 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. Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in >1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Uncomplicated Skin and Skin Structure Infections Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. All Other Indications Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Linezolid (n=248) Cefadroxil (n=251) Linezolid (n=215) Vancomycin (n=101) Diarrhea 7.8 8.0 10.8 12.1 Vomiting 2.9 6.4 9.4 9.1 Headache 6.5 4.0 0.9 0 Anemia 0 0 5.6 7.1 Thrombocytopenia 0 0 4.7 2.0 Nausea 3.7 3.2 1.9 0 Generalized abdominal pain 2.4 2.8 0.9 2.0 Localized abdominal pain 2.4 2.8 0.5 1.0 Loose stools 1.6 0.8 2.3 3.0 Eosinophilia 0.4 0.8 1.9 1.0 Pruritus at non-application site 0.8 0.4 1.4 2.0 Vertigo 1.2 0.4 0 0 Of the pediatric patients treated for uSSSIs, 1.6% 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 0.9% of linezolid-treated and 6.1% of comparator-treated patients. Laboratory Abnormalities : Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10%) with linezolid and 1.5% (range among studies: 0.4 to 7%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for linezolid; the role of linezolid in these events cannot be determined [see Warnings and Precautions ( 5.1 )]. Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differen