Linezolid

5 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 Linezolid Tablets concomitantly with serotonergic agents for signs of serotonin syndrome. If signs or symptoms of serotonin syndrome occur, consider discontinuing Linezolid Tablets and/or concomitant serotonergic agents. ( 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 Tablets 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 ) 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 concomitant use of linezolid and serotonergic agents have been reported. Commonly used serotonergic agents include serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, ‎ tricyclic antidepressants, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine. Symptoms associated with serotonin syndrome may include hyperthermia, diaphoresis, agitation, hyperreflexia, clonus, pyrexia, opsoclonus, muscle rigidity , tremor, and hypertonia.‎ Monitor patients for the emergence of serotonin syndrome with the concomitant use of Linezolid Tablets and ‎serotonergic agents or with use of Linezolid Tablets in patients with carcinoid syndrome. If signs or symptoms of ‎serotonin syndrome occur, consider discontinuing Linezolid Tablets and/or concomitant serotonergic agents as ‎clinically appropriate and initiate supportive treatment. Inform patients of the increased risk of serotonin ‎syndrome when Linezolid Tablets is used concomitantly with serotonergic agents.‎ 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 (16.0%); 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) ]. 5.5 Clostridioides difficile -Associated Diarrhea 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. 5.6 Potential Interactions Producing Elevation of Blood Pressure 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) ] . 5.7 Lactic Acidosis 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 should receive immediate medical evaluation. 5.8 Convulsions 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. 5.9 Rhabdomyolysis Rhabdomyolysis has been reported with the use of linezolid, including Linezolid Tablets [ 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 Tablets and initiate appropriate therapy. 5.10 Hypoglycemia 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 Tablets may be required. 5.11 Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Postmarketing cases of hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in patients treated with linezolid. In reported cases, the signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death. Monitor serum sodium levels regularly in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or SIADH while taking linezolid. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue linezolid, and institute appropriate supportive measures. 5.12 Development of Drug-Resistant Bacteria Prescribing linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS 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) ] 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 Greenstone LLC at 1-877-446-3679 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 2.0 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 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. 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 by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6–24 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 10.0%) with linezolid and 1.5% (range among studies: 0.4 to 7.0%) 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 differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7. Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal < 75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and of baseline for values abnormal at baseline. Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg every 12 hours Clarithromycin 250 mg every 12 hours Linezolid 600 mg every 12 hours 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. Hemoglobin (g/dL) 0.9 0.0 7.1 6.6 Platelet count (× 10 3 /mm 3 ) 0.7 0.8 3.0 1.8 WBC (× 10 3 /mm 3 ) 0.2 0.6 2.2 1.3 Neutrophils (× 10 3 /mm 3 ) 0.0 0.2 1.1 1.2 Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal > 2 × Upper Limit of Normal (ULN) for values normal at baseline; > 2 × ULN and >2 × baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg every 12 hours Clarithromycin 250 mg every 12 hours Linezolid 600 mg every 12 hours 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. AST (U/L) 1.7 1.3 5.0 6.8 ALT (U/L) 1.7 1.7 9.6 9.3 LDH (U/L) 0.2 0.2 1.8 1.5 Alkaline phosphatase (U/L) 0.2 0.2 3.5 3.1 Lipase (U/L) 2.8 2.6 4.3 4.2 Amylase (U/L) 0.2 0.2 2.4 2.0 Total bilirubin (mg/dL) 0.2 0.0 0.9 1.1 BUN (mg/dL) 0.2 0.0 2.1 1.5 Creatinine (mg/dL) 0.2 0.0 0.2 0.6 Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal < 75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; < 75% (<50% for neutrophils) of LLN and <75% (<50% for neutrophils, <90% for hemoglobin if baseline <LLN) of baseline for values abnormal at baseline. Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay 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 by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6–24 hours, depending on age and renal clearance. Linezolid Cefadroxil Linezolid Vancomycin Hemoglobin (g/dL) 0.0 0.0 15.7 12.4 Platelet count (× 10 3 /mm 3 ) 0.0 0.4 12.9 13.4 WBC (× 10 3 /mm 3 ) 0.8 0.8 12.4 10.3 Neutrophils (× 10 3 /mm 3 ) 1.2 0.8 5.9 4.3 Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal >2 × Upper Limit of Normal (ULN) for values normal at baseline; >2 × ULN and >2 (>1.5 for total bilirubin) × baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay 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 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/by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6–24 hours, depending on age and renal clearance. Linezolid Cefadroxil Linezolid Vancomycin ALT (U/L) 0.0 0.0 10.1 12.5 Lipase (U/L) 0.4 1.2 --- --- Amylase (U/L) --- --- 0.6 1.3 Total bilirubin (mg/dL) --- --- 6.3 5.2 Creatinine (mg/dL) 0.4 0.0 2.4 1.0 6.2 Postmarketing Experience 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.

<table ID="_Reftable2" width="100%"><caption>Table 2. Incidence (%) of Treatment&#x2013;Emergent Adverse Reactions Occurring in &gt;1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials</caption><col width="31%"/><col width="18%"/><col width="17%"/><col width="18%"/><col width="17%"/><thead><tr><th align="center" styleCode="Rrule Toprule " valign="bottom"><content styleCode="bold">ADVERSE REACTIONS</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Uncomplicated Skin and Skin Structure Infections</content></th><th align="center" colspan="2" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">All Other Indications</content></th></tr><tr><th align="left" styleCode="Rrule Botrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Linezolid</content> <content styleCode="bold">400 mg by mouth every 12 hours</content> <content styleCode="bold">(n=548)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Clarithromycin</content> <content styleCode="bold">250 mg by mouth every 12 hours</content> <content styleCode="bold">(n=537)</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">Linezolid</content> <content styleCode="bold">600 mg every 12 hours</content> <content styleCode="bold">(n=1498)</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">All Other Comparators</content><footnote ID="_Reft2f1">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.</footnote> <content styleCode="bold">(n=1464)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8.8</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8.4</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>5.7</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>4.4</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6.4</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4.6</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.3</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" valign="top"><paragraph>1.5</paragraph></td></tr><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>2.3</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>2.6</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.4</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Taste alteration</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.0</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vaginal moniliasis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Oral moniliasis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Abnormal liver function tests</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Fungal infection</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tongue discoloration</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Localized abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Generalized abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.0</paragraph></td></tr></tbody></table>

<table ID="_Reftable3" width="85%"><caption>Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in &gt; 1% of Pediatric Patients (and &gt;1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials</caption><col width="32%"/><col width="15%"/><col width="16%"/><col width="15%"/><col width="17%"/><thead><tr><th align="left" styleCode="Rrule Toprule " valign="bottom"><content styleCode="bold">ADVERSE REACTIONS</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Uncomplicated Skin and Skin Structure Infections</content><footnote ID="_Reft3f1">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.</footnote></th><th align="center" colspan="2" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">All Other Indications</content><footnote ID="_Reft3f2">Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6&#x2013;24 hours, depending on age and renal clearance.</footnote></th></tr><tr><th align="left" styleCode="Rrule Botrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Linezolid</content> <content styleCode="bold">(n=248)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cefadroxil</content> <content styleCode="bold">(n=251)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Linezolid</content> <content styleCode="bold">(n=215)</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">Vancomycin</content> <content styleCode="bold">(n=101)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7.8</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8.0</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>10.8</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>12.1</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.4</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9.1</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>7.1</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Generalized abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Localized abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Loose stools</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Eosinophilia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pruritus at non-application site</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.4</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vertigo</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_Reftable4" width="85%"><caption>Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal<footnote ID="_Reft4f1"><content styleCode="bold">&lt;</content>75% (&lt;50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; &lt;75% (&lt;50% for neutrophils) of LLN and of baseline for values abnormal at baseline.</footnote> Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid</caption><col width="26%"/><col width="17%"/><col width="18%"/><col width="17%"/><col width="18%"/><thead><tr><th align="left" styleCode="Rrule Toprule " valign="bottom"><content styleCode="bold">Laboratory Assay</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Uncomplicated Skin and Skin Structure Infections</content></th><th align="center" colspan="2" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">All Other Indications</content></th></tr><tr><th align="left" styleCode="Rrule Botrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Linezolid</content> <content styleCode="bold">400 mg every 12 hours</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Clarithromycin</content> <content styleCode="bold">250 mg every 12 hours</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Linezolid</content> <content styleCode="bold">600 mg every 12 hours</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">All Other Comparators</content><footnote ID="_Reft4f2">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.</footnote></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Hemoglobin (g/dL)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7.1</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>6.6</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Platelet count (&#xD7; 10³/mm³)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>WBC (&#xD7; 10³/mm³)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.3</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Neutrophils (&#xD7; 10³/mm³)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.2</paragraph></td></tr></tbody></table>