Averozolid


FDA Indications of AVEROZOLID:

(1) Skin and soft structure Infections (SSSls):

A) Complicated Skin and soft structure Infections including:

  • Diabetic foot infections.
  • Surgical site infections.
  • Deep abscess.
  • Infected ulcers, burn and wound.
  • Necrotizing soft tissue infections.

B) Uncomplicated Skin and soft structure Infections:

  • Abscess.
  • Carbuncle.
  • Impetigo.
  • Pyoderma.

Caused by all gram-positive bacteria including MRSA, VRSA and VRE.

(2) Pneumonia:

A) Post-operative nosocomial pneumonia. B) Community-aquired pneumonia.

(3) VRE (Vancomycin – Resistant Enterococci) causing:

  • Intra-abdominal infections.
  • Urinary Tract Infections.
  • Surgical wound infection.
  • Bacteremia.

Dosage:

1 Tab. (600 mg) / 12 hr for 10 – 14 days.

AVEROZOLID® has:

  • Oral bioavailability 100% (making oral is equally effective as I.V.).
  • No dosage adjustment for:
    • Oral or IV.
    • Age & Gender.
    • Relationship to meals.
    • Hepatic or renal impairment.
  • No significant side-effects in dosage of 600 mg / 12 hr for 28 days

Averozolid Tablets, and Averozolid for Oral Suspension contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.

The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:

Averozolid Tablets for oral administration contain 600 mg linezolid as film-coated compressed tablets. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na+) content is 2.92 mg per 600-mg tablet (0.1 mEq per tablet, regardless of strength).

Averozolid for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors . The sodium (Na+) content is 8.52 mg per 5 mL (0.4 mEq per 5 mL).

Averozolid formulations are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms. Linezolid 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.

Vancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremia.

Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]).

Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. Averozolid has not been studied in the treatment of decubitus ulcers.

Uncomplicated skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes.

Community-acquired pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]), including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible and -resistant strains).

DOSAGE AND ADMINISTRATION

The recommended dosage for Averozolid formulations for the treatment of infections is described in Table 4.

Table 4. Dosage Guidelines for Averozolid
InfectionDue to the designated pathogens Dosage and Route of Administration Recommended Duration of Treatment (consecutive days)
Adults and Adolescents (12 Years and Older)
Complicated skin and skin structure infections 600 mg oral q12h 10 to 14
Community-acquired pneumonia, including concurrent bacteremia
Nosocomial pneumonia
Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 600 mg oral q12h 14 to 28
Uncomplicated skin and skin structure infections Adults: 600 mg oral q12h 7 to 14

Adult patients with infection due to MRSA should be treated with Averozolid 600 mg q12h.

In controlled clinical trials, the protocol-defined duration of treatment for all infections ranged from 7 to 28 days. Total treatment duration was determined by the treating physician based on site and severity of the infection, and on the patient’s clinical response.

No dose adjustment is necessary when switching from intravenous to oral administration.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid for more than 28 days. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than four weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Averozolid.

Pregnancy

Pregnancy Category C

Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen. There are no adequate and well-controlled studies in pregnant women. Averozolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Linezolid and its metabolites ar” excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Averozolid is administered to a nursing woman.

Geriatric Use

Of the 2046 patients treated with Averozolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.

Averozolid formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

Monoamine Oxidase Inhibitors

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

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).

Potential Serotonergic Interactions

Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, 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 or buspirone.

Pharmacokinetics

Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.

Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean � Standard Deviation, n=16)

Absorption

Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment.

Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-?values is similar under both conditions.

Distribution

Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and for sweat relative to plasma was 0.55 to 1.

Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. Linezolid is not an inducer of cytochrome P450 (CYP) in rats, and it has been demonstrated from in vitro studies that linezolid is not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

Excretion

Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The renal clearance of linezolid is low (average 40 mL/min) and suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.

A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.

Special Populations

Geriatric

The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.

Gender

Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.

Renal Insufficiency

The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction. The clinical significance of accumulation of these two metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumul”tion of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by dialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour dialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.

Hepatic Insufficiency

The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic insufficiency (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated.

Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains.

In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10 -9 to 1 x 10 -11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published.1 In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred 2. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use.3 The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies.4, 5 Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described in the “NDICATIONS AND USAGE section.

Aerobic and facultative Gram-positive microorganisms

* Enterococcus faecium (vancomycin-resistant strains only) * Staphylococcus aureus (including methicillin-resistant strains) * Streptococcus agalactiae * Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1) * Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and facultative Gram-positive microorganisms

* Enterococcus faecalis (including vancomycin-resistant strains) * Enterococcus faecium (vancomycin-susceptible strains) * Staphylococcus epidermidis (including methicillin-resistant strains) * Staphylococcus haemolyticus * Viridans group streptococci Aerobic and facultative Gram-negative microorganisms

* Pasteurella multocida

Adult Patients

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

“”

Table 1. Incidence (%) of Drug-Related Adverse Events Occurring in >1% of Adult Patients Treated with Averozolid in Comparator-Controlled Clinical Trials
Uncomplicated Skin and Skin Structure Infections All Other Indications
Adverse Event Clarithromycin 250 mg PO q12h (n=537) Averozolid 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 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 Averozolid were nausea, headache, diarrhea, and vomiting. 2.4 2.1 1.7
Diarrhea 4.8 4.0 2.7
Nausea 3.5 3.3 1.8
Headache 2.2 1.9 1.0
Taste alteration 2.0 0.9 0.2
Vaginal moniliasis 1.3 1.0 0.4
Fungal infection 0.2 0.1 <0.1
Abnormal liver function tests 0 1.3 0.5
Vomiting 0.4 1.2 0.4
Tongue discoloration 0 0.2 0
Dizziness 1.5 0.4 0.3
Oral moniliasis 0 1.1 0.4

The safety and effectiveness of Averozolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years:

  • nosocomial pneumonia
  • complicated skin and skin structure infections
  • community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
  • vancomycin-resistant Enterococcus faecium infections
The safety and effectiveness of Averozolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years:
      uncomplicated skin and skin structure infections caused by Staphylococcus aureus ( methicillin-susceptible strains only) or Streptococcus pyogenes
Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, linezolid clearance is a function of age. Excluding neonates less than a week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and in systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for pediatric patients up to 11 years of age shou”d be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h.Recommendations for the dosage regimen for pre-term neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. Therefore, these pre-term neonates should be initiated with a dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of a 10 mg/kg q8h regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by 7 days of life.In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of 4 �g/mL treated with Averozolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 �g/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response.

Pediatric Patients

The safety of Averozolid 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 Averozolid 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 Averozolid in these trials.
Table 8. Incidence (%) of Adverse Events Reported in ?2% of Pediatric Patients Treated with Averozolid in Comparator-Controlled Clinical Trials
Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received Averozolid 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received Averozolid 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received Averozolid 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6�24h, depending on age and renal clearance.
Event Averozolid (n=248) Cefadroxil (n = 251) Averozolid (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 Averozolid 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received Averozolid 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received Averozolid 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6�24h, depending on age and renal clearance.
Averozolid (n=248) Cefadroxil (n=251) Averozolid (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

Averozolid 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 Averozolid 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 Averozolid 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 Averozolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of Averozolid 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 Averozolid; 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 Averozolid 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 Averozolid
Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications
Averozolid 400 mg q12h Clarithromycin 250 mg q12h Averozolid 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 Ch”mistry Laboratory Value in Comparator-Controlled Clinical Trials with Averozolid
Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications
Averozolid 400 mg q12h Clarithromycin 250 mg q12h Averozolid 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 Averozolid
Laboratory Assay Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received Averozolid 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received Averozolid 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received Averozolid 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6�24h, depending on age and renal clearance.
Averozolid Cefadroxil Averozolid 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 Averozolid
Laboratory Assay Uncomplicated Skin and Skin Structure InfectionsPatients 5 through 11 years of age received Averozolid 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received Averozolid 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received Averozolid 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6�24h, depending on age and renal clearance.
Averozolid Cefadroxil Averozolid 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

Pediatric

The pharmacokinetics of linezolid following a single IV dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 2 for the pediatric populations studied and healthy adult subjects after administration of single IV doses.

The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h). Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h (see DOSAGE AND ADMINISTRATION).

Table 2. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV; [Min, Max Values])
Age Group Cmax �g/mL Vss L/kg AUC AUC = Single dose AUC0�? �g � h/mL t1/2 hrs CL mL/min/kg
Cmax = Maximum plasma concentration; Vss= Volume of distribution; AUC = Area under concentration-time curve; t1/2 = Apparent elimination half-life; CL = Systemic clearance normalized for body weight
Neonatal Patients Pre-termIn this data set, “pre-term” is defined as <34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days) < 1 week (N=9) 1 12.7 (30%) [9.6, 22.2] 0.81 (24%) [0.43, 1.05] 108 (47%) [41, 191] 5.6 (46%) [2.4, 9.8] 2.0 (52%) [0.9, 4.0]
Full-term 2 < 1 week (N=10) 11.5 (24%) [8.0, 18.3] 0.78 (20%) [0.45, 0.96] 55 (47%) [19, 103] 3.0 (55%) [1.3, 6.1] 3.8 (55%) [1.5, 8.8]
Full-term ? 1 week to ? 28 days (N=10) 12.9 (28%) [7.7, 21.6] 0.66 (29%) [0.35, 1.06] 34 (21%) [23, 50] 1.5 (17%) [1.2, 1.9] 5.1 (22%) [3.3, 7.2]
Infant Patients > 28 days to < 3 Months (N=12) 11.0 (27%) [7.2, 18.0] 0.79 (26%) [0.42, 1.08] 33 (26%) [17, 48] 1.8 (28%) [1.2, 2.8] 5.4 (32%) [3.5, 9.9]
Pediatric Patients 3 months through 11 years (N=59) 15.1 (30%) [6.8, 36.7] 0.69 (28%) [0.31, 1.50] 58 (54%) [19, 153] 2.9 (53%) [0.9, 8.0] 3.8 (53%) [1.0, 8.5]
Adolescent Subjects and Patients 12 through 17 yearsDose of 600 mg or 10 mg/kg up to a maximum of 600 mg (N=36) 16.7 (24%) [9.9, 28.9] 0.61 (15%) [0.44, 0.79] 95 (44%) [32, 178] 4.1 (46%) [1.3, 8.1] 2.1 “53%) [0.9, 5.2]
Adult SubjectsDose normalized to 600 mg (N= 29) 12.5 (21%) [8.2, 19.3] 0.65 (16%) [0.45, 0.84] 91 (33%) [53, 155] 4.9 (35%) [1.8, 8.3] 1.7 (34%) [0.9, 3.3]

Tablets

Averozolid Tablets are available as follows:

600 mg (white, capsule-shaped, film-coated tablets)

Oral Suspension

Averozolid for Oral Suspension is available as a dry, white to off-white, orange-flavored granule/powder. When constituted as directed, each bottle will contain 60 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL.