Linezolid (Page 4 of 14)

Pediatric Patients

The safety of linezolid 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 one 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
*
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.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 mg/kg to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

ADVERSE REACTIONS

Uncomplicated Skin and Skin Structure Infections *

All Other Indications

Linezolid

(n = 248)

Cefadroxil

(n = 251)

Linezolid

(n = 215)

Vancomycin

(n = 101)

Diarrhea

7.8

8

10.8

12.1

Vomiting

2.9

6.4

9.4

9.1

Headache

6.5

4

0.9

0

Anemia

0

0

5.6

7.1

Thrombocytopenia

0

0

4.7

2

Nausea

3.7

3.2

1.9

0

Generalized abdominal pain

2.4

2.8

0.9

2

Localized abdominal pain

2.4

2.8

0.5

1

Loose stools

1.6

0.8

2.3

3

Eosinophilia

0.4

0.8

1.9

1

Pruritus at non-application site

0.8

0.4

1.4

2

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 Warning 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 * Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
*
< 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.
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.

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

Hemoglobin (g/dL)

0.9

0

7.1

6.6

Platelet count (x 10 3 /mm 3)

0.7

0.8

3

1.8

WBC (x 10 3 /mm 3)

0.2

0.6

2.2

1.3

Neutrophils (x 10 3 /mm 3)

0

0.2

1.1

1.2

Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal * Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
*
> 2 x Upper Limit of Normal (ULN) for values normal at baseline; > 2 x ULN and > 2 x baseline for values abnormal at baseline.
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.

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

AST (U/L)

1.7

1.3

5

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

Total bilirubin (mg/dL)

0.2

0

0.9

1.1

BUN (mg/dL)

0.2

0

2.1

1.5

Creatinine (mg/dL)

0.2

0

0.2

0.6

Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal * Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
*
< 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.
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.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 mg/kg to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

Laboratory Assay

Uncomplicated Skin and Skin Structure Infections

All Other Indications

Linezolid

Cefadroxil

Linezolid

Vancomycin

Hemoglobin (g/dL)

0

0

15.7

12.4

Platelet count (x 10 3 /mm 3)

0

0.4

12.9

13.4

WBC (x 10 3 /mm 3)

0.8

0.8

12.4

10.3

Neutrophils (x 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 * Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
*
> 2 x Upper Limit of Normal (ULN) for values normal at baseline; > 2 x ULN and > 2 (> 1.5 for total bilirubin) x baseline for values abnormal at baseline.
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.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously/by mouth every 8 hours or vancomycin 10 mg/kg to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

Laboratory Assay

Uncomplicated Skin and Skin Structure Infections

All Other Indications

Linezolid

Cefadroxil

Linezolid

Vancomycin

ALT (U/L)

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

2.4

1

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