Zyvox Drug Information

General Dosage and Administration

The recommended dosage for ZYVOX formulations for the treatment of infections is described in Table 1. Table 1. Dosage Guidelines for ZYVOX Infection Due to the designated pathogens Dosage, Route and Frequency of Administration Recommended Duration of Treatment (consecutive days) Pediatric Patients Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants.

All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life. (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia 10 mg/kg intravenously or oral Oral dosing using either ZYVOX Tablets or ZYVOX for Oral Suspension. every 8 hours No dose adjustment is necessary when switching from intravenous to oral administration.

Intravenous Administration ZYVOX I.V. Injection is supplied in single-dose, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration.

Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use.

Store at room temperature. Protect from freezing. ZYVOX I.V.

Injection may exhibit a yellow color that can intensify over time without adversely affecting potency. ZYVOX I.V. Injection should be administered by intravenous infusion over a period of 30 to 120 minutes.

Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If ZYVOX I.V.

Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. Discard unused portion. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of ZYVOX I.V.

Injection with an infusion solution compatible with ZYVOX I.V. Injection and with any other drug(s) administered via this common line.

Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

Incompatibilities

Physical incompatibilities resulted when ZYVOX I.V. Injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when ZYVOX I.V.

Injection was combined with ceftriaxone sodium.

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 ZYVOX 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. Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of ZYVOX-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event.

For all other indications, 20.4% of ZYVOX -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 ZYVOX. Table 2.

Incidence (%) of Treatment–Emergent Adverse Reactions Occurring in >1% of Adult Patients Treated with ZYVOX in Comparator-Controlled Clinical Trials % 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 ZYVOX-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.

These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. 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 ZYVOX-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event.

For all other indications, 18.8% of ZYVOX-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event. Table 3. Laboratory Abnormalities 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 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. 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. 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 Table 4. 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 Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal > 2 × Upper Limit of Normal (ULN) for values normal at baseline; > 2 × ULN and >2 × baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Table 6.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZYVOX. 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; • Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis. • Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia has been reported more often in patients with severe renal impairment and in patients with moderate to severe hepatic impairment; sideroblastic anemia. • Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision. • Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and ZYVOX. • Lactic acidosis.

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. • Convulsions. • Rhabdomyolysis. • Hypoglycemia, including symptomatic episodes. • Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). • 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.

Monoamine Oxidase Inhibitors Linezolid is a reversible, nonselective inhibitor of monoamine oxidase.

Adrenergic and Serotonergic Agents Linezolid has the potential for interaction with adrenergic and serotonergic agents.

Pregnancy Risk Summary Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.5 times (mice), equivalent to (rats), or 0.06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6.5 times the estimated human exposure.

When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6–16 (6.5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion.

Neither maternal nor embryo-fetal toxicities were observed at doses up to 150 mg/kg/day. Fetal malformations were not observed. The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights.

Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day. In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6–20 (0.06 times the estimated human exposure based on AUCs). Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

• Pediatric Use The safety and effectiveness of ZYVOX 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 ZYVOX 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 pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours. 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 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response.

Hypersensitivity

ZYVOX 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.

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 3,000 mg/kg/day and 2,000 mg/kg/day, respectively.