Zyvox (Linezolid) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Adult Patients

The safety of ZYVOX formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. In these studies, 85% of the adverse events reported with ZYVOX were described as mild to moderate in intensity. Table 6 shows the incidence of adverse events reported in at least 2% of patients in these trials. The most common adverse events in patients treated with ZYVOX were diarrhea (incidence across studies: 2.8% to 11.0%), headache (incidence across studies: 0.5% to 11.3%), and nausea (incidence across studies: 3.4% to 9.6%).

Table 6. Incidence (%) of Adverse Events Reported in ≥2% of Adult Patients in Comparator-Controlled Clinical Trials with ZYVOX

Event	ZYVOX (n=2046)	All Comparators Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; clarithromycin 250 mg PO q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h. (n=2001)
Diarrhea	8.3	6.3
Headache	6.5	5.5
Nausea	6.2	4.6
Vomiting	3.7	2.0
Insomnia	2.5	1.7
Constipation	2.2	2.1
Rash	2.0	2.2
Dizziness	2.0	1.9
Fever	1.6	2.1

Other adverse events reported in Phase 2 and Phase 3 studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.

Table 7 shows the incidence of drug-related adverse events reported in at least 1% of adult patients in these trials by dose of ZYVOX.

Table 7. Incidence (%) of Drug-Related Adverse Events Occurring in >1% of Adult Patients Treated with ZYVOX in Comparator-Controlled Clinical Trials

	Uncomplicated Skin and Skin Structure Infections		All Other Indications
Adverse Event	ZYVOX 400 mg PO q12h (n=548)	Clarithromycin 250 mg PO q12h (n=537)	ZYVOX 600 mg q12h (n=1498)	All Other ComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h. (n=1464)
% of patients with 1 drug-related adverse event	25.4	19.6	20.4	14.3
% of patients discontinuing due to drug-related adverse eventsThe most commonly reported drug-related adverse events leading to discontinuation in patients treated with ZYVOX were nausea, headache, diarrhea, and vomiting.	3.5	2.4	2.1	1.7
Diarrhea	5.3	4.8	4.0	2.7
Nausea	3.5	3.5	3.3	1.8
Headache	2.7	2.2	1.9	1.0
Taste alteration	1.8	2.0	0.9	0.2
Vaginal moniliasis	1.6	1.3	1.0	0.4
Fungal infection	1.5	0.2	0.1	<0.1
Abnormal liver function tests	0.4	0	1.3	0.5
Vomiting	0.9	0.4	1.2	0.4
Tongue discoloration	1.1	0	0.2	0
Dizziness	1.1	1.5	0.4	0.3
Oral moniliasis	0.4	0	1.1	0.4

Pediatric Patients

The safety of ZYVOX 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 these studies, 83% and 99%, respectively, of the adverse events reported with ZYVOX were described as mild to moderate in intensity. 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. Table 8 shows the incidence of adverse events reported in at least 2% of pediatric patients treated with ZYVOX in these trials.

Table 8. Incidence (%) of Adverse Events Reported in ≥2% of Pediatric Patients Treated with ZYVOX in Comparator-Controlled Clinical Trials

	Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h.		All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
Event	ZYVOX (n=248)	Cefadroxil (n = 251)	ZYVOX (n = 215)	Vancomycin (n=101)
Fever	2.9	3.6	14.1	14.1
Diarrhea	7.8	8.0	10.8	12.1
Vomiting	2.9	6.4	9.4	9.1
Sepsis	0	0	8.0	7.1
Rash	1.6	1.2	7.0	15.2
Headache	6.5	4.0	0.9	0
Anemia	0	0	5.6	7.1
Thrombocytopenia	0	0	4.7	2.0
Upper respiratory infection	3.7	5.2	4.2	1.0
Nausea	3.7	3.2	1.9	0
Dyspnea	0	0	3.3	1.0
Reaction at site of injection or of vascular catheter	0	0	3.3	5.1
Trauma	3.3	4.8	2.8	2.0
Pharyngitis	2.9	1.6	0.5	1.0
Convulsion	0	0	2.8	2.0
Hypokalemia	0	0	2.8	3.0
Pneumonia	0	0	2.8	2.0
Thrombocythemia	0	0	2.8	2.0
Cough	2.4	4.0	0.9	0
Generalized abdominal pain	2.4	2.8	0.9	2.0
Localized abdominal pain	2.4	2.8	0.5	1.0
Apnea	0	0	2.3	2.0
Gastrointestinal bleeding	0	0	2.3	1.0
Generalized edema	0	0	2.3	1.0
Loose stools	1.6	0.8	2.3	3.0
Localized pain	2.0	1.6	0.9	0
Skin disorder	2.0	0	0.9	1.0

Table 9 shows the incidence of drug-related adverse events 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 9. Incidence (%) of Drug-related Adverse Events Occurring in >1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials

Event	Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h.		All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
	ZYVOX (n=248)	Cefadroxil (n=251)	ZYVOX (n=215)	Vancomycin (n=101)
% of patients with ≥1 drug-related adverse event	19.2	14.1	18.8	34.3
% of patients discontinuing due to a drug-related adverse event	1.6	2.4	0.9	6.1
Diarrhea	5.7	5.2	3.8	6.1
Nausea	3.3	2.0	1.4	0
Headache	2.4	0.8	0	0
Loose stools	1.2	0.8	1.9	0
Thrombocytopenia	0	0	1.9	0
Vomiting	1.2	2.4	1.9	1.0
Generalized abdominal pain	1.6	1.2	0	0
Localized abdominal pain	1.6	1.2	0	0
Anemia	0	0	1.4	1.0
Eosinophilia	0.4	0.4	1.4	0
Rash	0.4	1.2	1.4	7.1
Vertigo	1.2	0.4	0	0
Oral moniliasis	0	0	0.9	4.0
Fever	0	0	0.5	3.0
Pruritus at non-application site	0.4	0	0	2.0
Anaphylaxis	0	0	0	10.1These reports were of 'red-man syndrome', which were coded as anaphylaxis.

Laboratory Changes

ZYVOX 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 ZYVOX 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 ZYVOX 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 ZYVOX and 0.4% with cefadroxil. Thrombocytopenia associated with the use of ZYVOX 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 ZYVOX; the role of linezolid in these events cannot be determined (see WARNINGS).

Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between ZYVOX 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 10, 11, 12, and 13.

Table 10. 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 ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure Infections		All Other Indications
	ZYVOX 400 mg q12h	Clarithromycin 250 mg q12h	ZYVOX 600 mg q12h	All Other ComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h.
Hemoglobin (g/dL)	0.9	0.0	7.1	6.6
Platelet count (x 103/mm3)	0.7	0.8	3.0	1.8
WBC (x 103/mm3)	0.2	0.6	2.2	1.3
Neutrophils (x 103/mm3)	0.0	0.2	1.1	1.2

Table 11. Percent of Adult Patients who Experienced at Least One Substantially Abnormal>2 x Upper Limit of Normal (ULN) for values normal at baseline;
>2 x ULN and >2 x baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure Infections		All Other Indications
	ZYVOX 400 mg q12h	Clarithromycin 250 mg q12h	ZYVOX 600 mg q12h	All Other ComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h.
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 12. 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 ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h.		All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
	ZYVOX	Cefadroxil	ZYVOX	Vancomycin
Hemoglobin (g/dL)	0.0	0.0	15.7	12.4
Platelet count (x 103/mm3)	0.0	0.4	12.9	13.4
WBC (x 103/mm3)	0.8	0.8	12.4	10.3
Neutrophils (x 103/mm3)	1.2	0.8	5.9	4.3

Table 13. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal>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. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h.		All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
	ZYVOX	Cefadroxil	ZYVOX	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

Postmarketing Experience

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during postmarketing use of ZYVOX (see WARNINGS). Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with ZYVOX. Lactic acidosis has been reported with the use of ZYVOX (see PRECAUTIONS). 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 ZYVOX (see PRECAUTIONS). Convulsions have been reported with the use of ZYVOX (see PRECAUTIONS). Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens Johnson syndrome have been reported. Superficial tooth discoloration has been reported with the use of linezolid. The discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to ZYVOX, or a combination of these factors. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO ZYVOX

Possible Zyvox side effects / adverse reactions in 86 year old female

Reported by a pharmacist from United States on 2007-01-03

Patient: 86 year old female

Reactions: Thrombocytopenia

Adverse event resulted in: hospitalization

Suspect drug(s):
Heparin
    Dosage: 5000 units bid sq
    Indication: Atrial Fibrillation
    Start date: 2005-12-21
    End date: 2005-12-24

Zyvox
    Dosage: 600 mg q12 iv
    Indication: Urosepsis
    Start date: 2005-12-26
    End date: 2006-01-04

Possible Zyvox side effects / adverse reactions in 79 year old male

Reported by a pharmacist from United Kingdom on 2007-01-11

Patient: 79 year old male

Reactions: Blood Potassium Increased

Suspect drug(s):
Zyvox
    Indication: Lower Respiratory Tract Infection

Zyvox
    Indication: Sepsis

Imipenem

Ramipril

Other drugs received by patient: Drug, Unspecified

Possible Zyvox side effects / adverse reactions in 74 year old female

Reported by a pharmacist from United States on 2007-01-16

Patient: 74 year old female weighing 33.0 kg (72.6 pounds)

Reactions: Dystonia, Pain, Sepsis

Suspect drug(s):
Celexa
    Dosage: 20 mg daily po [several months]
    Administration route: Oral
    Indication: Depression

Zyvox
    Dosage: 600 mg bid po
    Administration route: Oral
    Indication: Drug USE FOR Unknown Indication
    Start date: 2006-12-05