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.
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. For all 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.
|ADVERSE REACTIONS||Linezolid 600 mg every 12 hours|
(n = 1498)
|All Other Comparators*|
(n = 1464)
|Abnormal liver function tests||1.6||0.8|
|Localized abdominal pain||1.2||0.8|
|Generalized abdominal pain||1.2||1.0|
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.
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.
For all 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.
(n = 215)
(n = 101)
|Generalized abdominal pain||0.9||2.0|
|Localized abdominal pain||0.5||1.0|
|Pruritus at non-application site||1.4||2.0|
For all indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients.
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.
600 mg every 12 hours
|All Other Comparators†|
|Platelet count (× 103/mm3)||3.0||1.8|
|WBC (× 103/mm3)||2.2||1.3|
|Neutrophils (× 103/mm3)||1.1||1.2|
600 mg every 12 hours
|All Other Comparators†|
|Alkaline phosphatase (U/L)||3.5||3.1|
|Total bilirubin (mg/dL)||0.9||1.1|
|Platelet count (× 103/mm3)||12.9||13.4|
|WBC (× 103/mm3)||12.4||10.3|
|Neutrophils (× 103/mm3)||5.9||4.3|
|Total bilirubin (mg/dL)||6.3||5.2|
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval 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:
- Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) [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)].
- 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.
- 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)].
- Convulsions [see Warnings and Precautions (5.8)].
- Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.
- 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.
- Hypoglycemia, including symptomatic episodes [see Warnings and Precautions (5.9)].
- Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.10)].