Zyvox For Oral Susp

— THERAPEUTIC CATEGORIES —
  • Bacterial infections
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Zyvox For Oral Susp Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Linezolid 100mg/5mL; pwd for reconstitution; orange flavor; contains phenylalanine.

    Pharmacological Class

    Oxazolidinone.

    See Also

    How Supplied

    Tabs—20, 30; Susp—150mL; Infusion bags (100mL, 300mL)—10

    How Supplied

    ZYVOX 600 mg Tablets

    • Each tablet is white, capsule-shaped, film-coated and debossed with “ZYV” on one side and “600” on the other.

    • Available as 20 tablets in a HDPE bottle; or in unit dose packages of 30 tablets.

    ZYVOX IV Injection

    • Available in single-dose, ready-to-use flexible plastic infusion bags in a foil laminate overwrap.

    • The infusion bags and ports are not made with natural rubber latex.

    • Zyvox IV Injection is available in 10-count infusion bags containing either 200mg/100mL or 600mg/300mL of linezolid.

    ZYVOX for Oral Suspension

    • Available as a dry, white to off-white, orange-flavored granule/powder.

    • Once constituted, each bottle contains 150mL of suspension providing the equivalent of 100 mg of linezolid per each 5 mL.

    • Available as 100mg/5mL in 240mL glass bottles.

    Storage

    Store at 25ºC (77ºF). Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.

    Manufacturer

    Pfizer Inc.

    Generic Availability

    YES

    Mechanism of Action

    Linezolid is a synthetic agent of the oxazolidinone class, which has clinical utility in the treatment of infections caused by aerobic Gram (+) bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram (–) bacteria and anaerobic bacteria. 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 essential for bacterial reproduction. 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 isolates.

    Zyvox For Oral Susp Indications

    Indications

    Susceptible vancomycin-resistant E. faecium (VREF) infections, nosocomial and community-acquired pneumonia, complicated skin and skin structure infections (including diabetic foot infections) without osteomyelitis, uncomplicated skin and skin structure infections.

    Limitations of Use

    Not for treating Gram (–) infections. Safety and efficacy of Zyvox given for longer than 28 days have not been evaluated.

    Zyvox For Oral Susp Dosage and Administration

    Adult

    Infuse inj over 30–120 mins; switch to oral form when appropriate. VREF: 600mg every 12hrs for 14–28 days. Pneumonia, complicated skin and skin structure: 600mg every 12hrs for 10–14 days. Uncomplicated skin and skin structure (oral forms only): 12–17yrs: 600mg every 12hrs; >17yrs: 400mg every 12hrs; both for 10–14 days. MRSA: 600mg every 12hrs.

    Children

    Infuse inj over 30–120 mins; switch to oral form when appropriate. Neonates <7 days: see full labeling. 0–11yrs: VREF: 10mg/kg every 8hrs for 14–28 days; pneumonia, complicated skin and skin structure: 10mg/kg every 8hrs for 10–14 days. Uncomplicated skin and skin structure (oral forms only): <5yrs: 10mg/kg every 8hrs; 5–11yrs: 10mg/kg every 12hrs; both for 10–14 days.

    Administration

    • Administer Zyvox IV injection via IV infusion over 30 to 120 minutes. Do not use this IV infusion bag in series connections. Do not introduce additives to this solution. 

    • If Zyvox IV injection is to be administered concomitantly with another drug, each drug should be given separately. If the same IV line is used for several drugs, then flush the line before and after infusion with Zyvox IV injection with a compatible infusion solution.

    Zyvox For Oral Susp Contraindications

    Contraindications

    During or within 2 weeks of MAOIs (eg, phenelzine, isocarboxazid).

    Zyvox For Oral Susp Boxed Warnings

    Not Applicable

    Zyvox For Oral Susp Warnings/Precautions

    Warnings/Precautions

    Not for treating catheter-related bloodstream infections or catheter-site infections. Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome: not recommended. History of seizures. Monitor CBC's weekly (esp. on linezolid therapy for >2 weeks, those with pre-existing myelosuppression, severe renal impairment or moderate to severe hepatic impairment, concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial therapy). Consider discontinuing if myelosuppression occurs or worsens. Therapy >28 days. Peripheral and optic neuropathy. Monitor visual function if treatment ≥3 months and if new visual symptoms occur. Diabetes; monitor for hypoglycemia, if occurs, reduce dose or discontinue. Hyponatremia and/or SIADH; monitor serum sodium levels (esp. in elderly, those on diuretics, others at risk of). Phenylketonuria (oral susp form). Pregnancy. Nursing mothers: monitor infants.

    Warnings/Precautions

    Myelosuppression

    • Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported.

    • Monitor CBCs weekly especially in patients who receive linezolid for >2 weeks, those with pre-existing myelosuppression, severe renal impairment or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy.

    • Consider discontinuing Zyvox if myelosuppression develops or worsens.

    Peripheral and Optic Neuropathy

    • Peripheral and optic neuropathies have been reported, primarily in those receiving treatment for greater than 28 days. Visual blurring has been reported in those receiving treatment for less than 28 days.

    • Perform ophthalmic evaluation if symptoms of visual impairment develop (eg, changes in visual acuity, changes in color vision, blurred vision, or visual field defect).

    • Monitor visual function if treatment ≥3 months and if new visual symptoms occur. If peripheral or optic neuropathy occurs, assess the risks/benefits for the continued use of Zyvox.

    Serotonin Syndrome 

    • Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of Zyvox and serotonergic agents, including antidepressants such as SSRIs, have been reported. 

    • Monitor for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NSM-like) reactions. Unless clinically appropriate, do not administer linezolid to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine.

    • 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, promptly discontinue the serotonergic antidepressant and administer linezolid. Monitor patients for 2 weeks (5 weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. 

    Mortality Imbalance in an Investigational Study in Patients with Catheter-Related Bloodstream  Infections, Including Those with Catheter-site Infections 

    • 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.

    Clostridioides difficile-Associated Diarrhea (CDAD)

    • CDAD has been reported with nearly all antibacterial agents, including Zyvox.

    • Must consider CDAD in all patients who present with diarrhea after antibacterial drug use.

    • If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. 

    Potential Interactions Producing Elevation of Blood Pressure

    • Do not administer linezolid to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (eg, pseudoephedrine), vasopressive agents (eg, epinephrine, norepinephrine), dopaminergic agents (eg, dopamine, dobutamine).

    Lactic Acidosis 

    • Give immediate medical evaluation to patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Zyvox.

    Convulsions

    • Convulsions have been reported in patients treated with linezolid. Some cases were reported in those with a history of seizures or risk factors for seizures.

    Hypoglycemia

    • Exercise caution in diabetic patients due to the potential for hypoglycemic reactions when treated with linezolid.

    • If hypoglycemia occurs, it may require a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuing the oral hypoglycemic agent, insulin, or linezolid.

    Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

    • Postmarketing cases of hyponatremia and/or SIADH have been observed.

    • The signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death.

    • Monitor serum sodium levels frequently in the elderly, in those taking diuretics, and in patients at risk for hyponatremia and/or SIADH during treatment. Discontinue Zyvox if hyponatremia and/or SIADH occur, and institute appropriate supportive measures.

    Risks in Patients with Phenylketonuria (PKU)

    • Phenylalanine can be harmful to patients with PKU. Zyvox for Oral Suspension contains phenylalanine, a component of aspartame.

    • Each 5 mL of the 100 mg/5 mL oral suspension contains 20 mg of phenylalanine.

    Pregnancy Considerations

    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.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for linezolid and any potential adverse effects on the breastfed child from linezolid or from the underlying maternal condition.

    Clinical Considerations

    • Monitor the breastfed infant for diarrhea and vomiting.

    Pediatric Considerations

    The safety and efficacy of Zyvox for the treatment of pediatric patients from birth to 11 years of age have been established for the following infections:

    • Nosocomial pneumonia

    • Complicated skin and skin structure infections

    • Community-acquired pneumonia 

    • Vancomycin-resistant Enterococcus faecium infections

    The safety and efficacy of Zyvox for the treatment of pediatric patients from 5 to 17 years of age has been established for:

    • Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes

    Zyvox For Oral Susp Pharmacokinetics

    Absorption

    Absolute bioavailability: ~100%.

    Cmax (mcg/mL) (standard deviation): 21.20 (5.78) for tablet; 15.10 (2.52) for IV inj; 11.00 (2.76) for oral susp.

    Tmax (hrs) (standard deviation): 1.03 (0.62) for tablet; 0.51 (0.03) for IV inj; 0.97 (0.88) for oral susp.

    Distribution

    Volume of distribution at steady-state: 40–50 L.

    Plasma protein bound (concentration-independent): ~31%.

    Metabolism

    Primarily metabolized by oxidation of the morpholine ring.

    Elimination

    Nonrenal (~65%), renal (~30%), fecal (~6%). Mean renal clearance: 40 mL/min.

    Half-life (hrs) (standard deviation): 5.40 (2.06) for tablets; 4.80 (1.70) for IV inj; 4.60 (1.71) for oral susp.

    Systemic clearance (mL/min) (standard deviation): 80 (29) for tablets; 123 (40) for IV inj; 141 (45) for oral susp.

    Zyvox For Oral Susp Interactions

    Interactions

    See Contraindications. Concomitant sympathomimetics (eg, pseudoephedrine), vasopressive agents (eg, epinephrine, norepinephrine), dopaminergics (eg, dopamine, dobutamine): not recommended. Risk of serotonin syndrome with concomitant SSRIs, trycyclic antidepressants, bupropion, buspirone, triptans, or opioids (eg, meperidine). Avoid large amounts of dietary tyramine (keep <100mg/meal). May be antagonized by carbamazepine, phenytoin, phenobarbital. Caution with myelosuppressants.

    Zyvox For Oral Susp Adverse Reactions

    Adverse Reactions

    Diarrhea, vomiting, nausea, anemia, headache, rash, dizziness, pruritus, tongue discoloration, taste alteration; myelosuppression (eg, anemia, thrombocytopenia), lactic acidosis, C. difficile-associated diarrhea, hypoglycemia, blurred vision, convulsions.

    Zyvox For Oral Susp Clinical Trials

    Clinical Trials

    Adults

    Nosocomial Pneumonia

    • A randomized, multicenter, double-blind trial evaluated the efficacy and safety of Zyvox IV Injection in adults with clinically and radiologically documented nosocomial pneumonia. Patients were randomly assigned 1:1 to receive either Zyvox IV Injection (n=203) 600mg every 12 hours or vancomycin (n=193) IV 1g every 12 hours for 7 to 21 days. Both groups received concomitant aztreonam (1 to 2g every 8 hours IV). 

    • Of the study participants, 122 linezolid-treated patients and 103 vancomycin-treated patients were clinically evaluable. The cure rates were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients.

    • The following cure rates were observed at the test-of-cure visit for microbiologically evaluable adults with nosocomial pneumonia for the Zyvox and vancomycin treatment arms, respectively:

      • Staphylococcus aureus: 61% vs 61%.

      • Methicillin-resistant S. aureus: 59% vs 70%.

      • Streptococcus pneumoniae: 100% vs 90%.

    Complicated Skin and Skin Structure Infections

    • A randomized, multicenter, double-blind, double-dummy trial evaluated the efficacy and safety of Zyvox IV Injection in adults with clinically documented complicated skin and skin structure infections for a total of 10 to 21 days of treatment. Patients were randomly assigned to receive either Zyvox IV Injection (n=203) 600mg every 12 hours; or Zyvox Tablets (n=193) 600mg every 12 hours; or oxacillin IV 2g every 6 hours followed by dicloxacillin 500mg every 6 hours orally. Concomitant aztreonam was administered if clinically indicated.

    • Of the study participants, 245 linezolid-treated patients and 242 oxacillin-treated patients were clinically evaluable. The cure rates were 90% for linezolid-treated patients and 85% for oxacillin-treated patients. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients.

    • The following cure rates were observed at the test-of-cure visit for microbiologically evaluable adults with complicated skin and skin structure infections for the Zyvox and oxacillin/dicloxacillin treatment arms, respectively:

      • Staphylococcus aureus: 88% vs 86%.

      • Methicillin-resistant S. aureus: 67% vs (-)%.

      • Streptococcus agalactiae: 100% vs 50%.

      • Streptococcus pyogenes: 69% vs 75%.

    Diabetic Foot Infections

    • A randomized, multicenter, open-label trial evaluated the efficacy and safety of Zyvox IV Injection in adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infections”) for a total of 14 to 28 days of treatment. 

    • Patients were randomly assigned to receive Zyvox IV or orally 600mg every 12 hours; or ampicillin/sulbactam 1.5 to 3g IV; or amoxicillin/clavulanate 500 to 875mg every 8 to 12 hours orally. If ampicillin/sulbactam was not marketed, amoxicillin/clavulanate 500mg to 2g every 6 hours was used. 

    • Patients in the comparator group could also be treated with vancomycin 1g every 12 hours IV if MRSA was isolated from the foot infection. In either treatment groups, patients who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2g every 8-12 hours IV. There were 212 linezolid-treated patients and 105 comparator-treated patients who were clinically evaluable.

    • In the ITT population, the cure rates were 68.5% in linezolid-treated patients and 64% in the comparator-treated patients. In the clinically evaluable patients, the cure rates were 83% in linezolid-treated patients and 73% in comparator-treated patients.

    • The following cure rates were observed at the test-of-cure visit for microbiologically evaluable adults with diabetic foot infections for the Zyvox and comparator treatment arms, respectively:

      • Staphylococcus aureus: 78% vs 69%.

      • Methicillin-resistant S. aureus: 71% vs 67%.

      • Streptococcus agalactiae: 86% vs 56%.

    Vancomycin-Resistant Enterococcal Infections

    • A randomized, multicenter, double-blind trial evaluated the efficacy and safety of a Zyvox in adults with documented or suspected vancomycin-resistant enterococcal infection. The trial compared a high dose of Zyvox (600mg) (n=79) to a low dose of Zyvox (200mg) (n=66) given every 12 hours either IV or orally for 7 to 28 days. All patients could receive concomitant aztreonam or aminoglycosides.

    • The ITT population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm.

    • The following cure rates were observed at the test-of-cure visit for ITT adults with documented vancomycin-resistant enterococcal infections for the Zyvox 600mg and Zyvox 200mg treatment arms, respectively:

      • Any site: 67% vs 52%.

      • Any site with associated bacteremia: 59% vs 29%.

      • Bacteremia of unknown origin: 50% vs 29%.

      • Skin and skin structure: 69% vs 100%.

      • Urinary tract: 63% vs 60%.

      • Pneumonia: 67% vs 0%.

      • Other (includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection): 85% vs 39%.

     

    Pediatric Patients

    Infections due to Gram-positive Bacteria

    • A randomized, open-label, comparator-controlled clinical study evaluated the efficacy and safety of Zyvox in pediatric patients ranging in age from birth to 11 years with infections caused by the documented or suspected Gram-positive bacteria.

    • One group of patients received Zyvox IV Injection 10mg/kg every 8 hours followed by Zyvox for Oral Suspension 10mg/kg every 8 hours. Another group received vancomycin 10 to 15 mg/kg IV every 6 to 24 hours, based on age and renal clearance. The third arm of the study included patients with a confirmed vancomycin-resistant Enterococcus faecium (VRE) infections and received Zyvox 10m/kg every 8 hours IV and/or orally. Treatment duration for all patients was for a total of 10 to 28 days.

    • In the ITT population, there were 206 linezolid-treated patients and 102 vancomycin-treated patients.

    • The following cure rates were observed at the test-of-cure visit for pediatric patients in the ITT population for the Zyvox and vancomycin treatment arms, respectively:

      • Any diagnosis: 81% vs 83%.

      • Complicated skin and skin structure infections: 85% vs 91%.

      • Nosocomial pneumonia: 72% vs 92%.

    • The following cure rates were observed at the test-of-cure visit for pediatric patients in the MITT population (defined as ITT patients with an isolated Gram-positive pathogen at baseline) for the Zyvox and vancomycin treatment arms, respectively:

      • Any diagnosis: 80% vs 90%.

      • Complicated skin and skin structure infections: 86% vs 96%.

      • Nosocomial pneumonia: 83% vs 100%.

    • The following cure rates were observed at the test-of-cure visit for pediatric patients in the clinically evaluable population for the Zyvox and vancomycin treatment arms, respectively:

      • Any diagnosis: 91% vs 91%.

      • Complicated skin and skin structure infections: 94% vs 96%.

      • Nosocomial pneumonia: 100% vs 100%.

    Zyvox For Oral Susp Note

    Not Applicable

    Zyvox For Oral Susp Patient Counseling

    Patient Counseling

    Peripheral and Optic Neuropathy

    • Advise patients to inform their physician if they experience changes in vision during treatment.

    Serotonin Syndrome

    • Advise patients to inform their physician if they are taking serotonergic agents (eg, serotonin re-uptake inhibitors or other antidepressants and opioids).

    Potential Interactions Producing Elevation of Blood Pressure

    • Inform physician if they have a history of hypertension.

    • Avoid large quantities of foods or beverages with high tyramine content during treatment. Examples of foods high in tyramine content: those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses, fermented or air-dried meats, sauerkraut, soy sauce, tap beers, and red wines.

    • Inform physician if they are taking drugs containing pseudoephedrine HCl or phenylpropanolamine HCl (eg, cold remedies and decongestants).

    Lactic Acidosis

    • Inform physician if repeated episodes of nausea or vomiting during treatment.

    Convulsions

    • Inform physician if patient has a history of seizures or convulsions.

    Hypoglycemia

    • Inform physician if patient has diabetes mellitus. Contact healthcare provider or physician if hypoglycemic reactions occur.

    Hyponatremia and/or SIADH

    • Inform physician if signs/symptoms of hyponatremia and/or SIADH occur.

    Phenylketonuria

    • Advise patients that each 5mL of the 100mg/5 mL Zyvox for Oral Suspension contains 20 mg phenylalanine.

    Infertility

    • Advise male patients that Zyvox may reversibly impair fertility.

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