Linezolid (Page 2 of 7)

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, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone [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 0.970, 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 Clostridium difficile Associated Diarrhea

Clostridium 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic 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 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 may be required.

5.10 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

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 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

*
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.

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 * (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 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

*
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 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 >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 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 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 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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