INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ZYVOXID

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ZYVOXID

ZYVOXID 400 mg (Tablets)
ZYVOXID 600 mg (Tablets)
ZYVOXID 200 mg/100 mL (Solution for Infusion)
ZYVOXID 600 mg/300 mL (Solution for Infusion)
ZYVOXID 20 mg/mL (Granules for Suspension)

COMPOSITION:
ZYVOXID 400 mg Tablets: Each film coated tablet contains 400 mg linezolid.
ZYVOXID 600 mg Tablets: Each film coated tablet contains 600 mg linezolid.
ZYVOXID 200 mg/100 mL Solution for Infusion: Each 1 mL contains 2 mg linezolid. The 100 mL infusion bag contains 200 mg linezolid.
ZYVOXID 600 mg/300 mL Solution for Infusion: Each 1 mL contains 2 mg linezolid. The 300 mL infusion bag contains 600 mg linezolid.
ZYVOXID 20 mg/mL Granules for Suspension: Following reconstitution with 123 mL water, each 1 mL contains 20 mg linezolid. Preservative content: Sodium benzoate 0,2% m/v.

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1 Broad and medium spectrum antibiotic

PHARMACOLOGICAL ACTION:
Pharmacodynamics
Linezolid is a synthetic antibacterial agent of the oxazolidinone class of antibiotics. It has in vitro activity against aerobic Gram positive bacteria, certain Gram negative bacteria and anaerobic microorganisms. It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex that is an essential component of the translation process.
The in vitro post-antibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAEs were 3,6 and 3,9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter for efficacy was the time that the linezolid plasma levels exceeded the minimum inhibitory concentration (MIC) of the infecting organism. Linezolid was efficacious when plasma levels exceeded the MIC of the infecting organism for a minimum of 40% of the dosing interval.
Susceptibility: The following gives an approximate guidance on the probabilities as to whether microorganisms will be susceptible to linezolid or not. (Only microorganisms relevant to the given clinical indications are presented.)

Category
Susceptible organisms
Gram positive aerobes:         Corynebacterium jeikeium         Enterococcus casseliflavus         Enterococcus faecalis (including         glycopeptide resistant strains) *         Enterococcus faecium (including         glycopeptide resistant strains) *         Enterococcus gallinarum         Listeria monocytogenes         Staphylococcus aureus (including         methicillin resistant strains) *         Staphylococcus aureus (glycopeptide         intermediate strains)         Staphylococcus epidermidis (including         methicillin resistant strains) *         Staphylococcus haemolyticus         Staphylococcus lugdunensis	Streptococcus agalactiae * Streptococcus intermedius Streptococcus pneumoniae (including penicillin intermediate and resistant strains) * Streptococcus pyogenes * Group C streptococci Group G streptococci Viridans group streptococci
Gram negative aerobes:         Pasteurella canis	Pasteurella multocida
Gram positive anaerobes:         Clostridium perfringens         Peptostreptococcus species	Peptostreptococcus anaerobius
Gram negative anaerobes:         Bacteroides fragilis	Prevotella species
Other:         Chlamydia pneumoniae
Intermediately susceptible organisms
Legionella species         Mycoplasma species	Moraxella catarrhalis
Resistant organisms
Haemophilus influenzae         Enterobacteriaceae	Neisseria species Pseudomonas species

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
Resistance: Linezolid’s mechanism of action differs from that of other antibiotics (e.g. the aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptogramins, tetracyclines and chloramphenicol). Therefore, there is no cross-resistance between linezolid and these classes of drugs.
In vitro studies have shown that resistance to linezolid develops slowly via multiple step mutations in 23S ribosomal RNA and occurs at frequencies of less than 1 x 10^-9 to 1 x 10^-11.
Pharmacokinetics
ZYVOXID primarily contains linezolid that is biologically active and is metabolised to form inactive metabolites. The aqueous solubility of linezolid is approximately 3 mg/mL and is independent of pH between pH 3 to 9.
Absorption:
Maximum plasma concentrations are reached within 2 hours of dosing and absolute bioavailability is approximately 100%. It is not affected by food.
Distribution:
The volume of distribution at steady-state averages at about 40 to 50 liters in healthy adults and approximates to total body water. Plasma protein binding is about 31%.
Linezolid concentrations have been determined in various fluids from a limited number of subjects in volunteer studies following multiple dosing. The ratio of linezolid in saliva and sweat relative to plasma was 1,2:1,0 and 0,55:1,0 respectively. The ratio for epithelial lining fluid and alveolar cells of the lung was 4,5:1,0 and 0,15:1,0, when measured at steady-state Cmax respectively. In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0,7:1,0 after linezolid dosing.
Metabolism:
Linezolid is metabolised by a non-enzymatic process. Metabolic oxidation of the morpholine ring results primarily in two inactive open-ring carboxylic acid derivatives. The hydroxyethyl glycine metabolite (B) is the predominant human metabolite and the amino ethoxy acetic acid metabolite (A) is less abundant. Linezolid is not detectably metabolised by cytochrome P450 (CYP) isoenzymes in vitro and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Linezolid does not significantly induce major cytochrome P450 isoenzymes in rats and does not induce human CYP2C9.
Elimination:
Under steady-state conditions, linezolid is primarily excreted in the urine as metabolite B (40%), parent drug (30-35%) and metabolite A (10%). The elimination half-life of the parent drug averages at about 5-7 hours. Non-renal clearance accounts for approximately 65% of the total clearance of linezolid.
Special populations:
Elderly:
The pharmacokinetics of linezolid is not significantly altered in elderly patients aged 65 and over.
Renal insufficiency:
No dose adjustment is necessary in patients with either mild, moderate or severe renal insufficiency, as linezolid clearance is independent of creatinine clearance. There is evidence that the primary metabolites of linezolid accumulate in patients with severe renal insufficiency (i.e. CLCR <30 mL/min). The clinical significance of this has not yet been established. As approximately 30% of a dose is removed during 3 hours of haemodialysis (beginning 3 hours after administration), ZYVOXID should be given after dialysis in patients receiving such treatment.
Hepatic insufficiency:
The pharmacokinetics of linezolid are not altered in patients with mild to moderate hepatic insufficiency. Dose adjustment in such patients is, therefore, not required. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency has not been evaluated. However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.
Children:
Currently there are only limited data on the pharmacokinetics of single and multiple dosing of linezolid in paediatric patients of all ages. The pharmacokinetics in children below the age of 3 months have not been established.
Paediatric dosing regimens that provide a pharmacokinetic profile similar to adults have not been determined.

INDICATIONS:
ZYVOXID formulations are indicated for the treatment of adult patients with the following infections caused by susceptible strains of the designated micro-organisms (see PHARMACOLOGICAL ACTION):
Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteraemia.
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (penicillin-susceptible strains only). Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.
Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOXID has not been studied in the treatment of diabetic foot and decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.
Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes.
Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteraemia, or Staphylococcus aureus (methicillin-susceptible strains only).
Due to concern about inappropriate use of antibiotics leading to an increase in resistant organisms, prescribers should carefully consider alternatives before initiating treatment with ZYVOXID in the outpatient setting.
Appropriate specimens for bacteriological examination should be obtained in order to isolateand identify the causative organisms and to determine their susceptibility to linezolid. Therapy may be instituted empirically while awaiting results of these tests. Once these results become available, antimicrobial therapy should be adjusted accordingly.

CONTRA-INDICATIONS:
ZYVOXID formulations are contra-indicated for use in

-	Patients who have known hypersensitivity to linezolid or any excipients.
-	Patients on monoamine oxidase inhibitors.
-	Pregnancy and lactation as the safety has not been demonstrated.

WARNINGS:
Pseudomembranous colitis has been reported. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of this antibacterial agent.
Thrombocytopenia that may be dependent on duration of therapy has been reported. Monitoring of platelet counts should be considered for patients who have pre-existing thrombocytopenia, who receive concomitant medication that may decrease platelet count or function, or who receive linezolid for more than 2 weeks.
The use of antibiotics may result in an overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.
ZYVOXID has not been studied in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.

DOSAGE AND DIRECTIONS FOR USE:
ZYVOXID tablets, oral suspension or solution for infusion may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.
The solution for infusion should be administered over a period of 30 to 120 minutes. The film coated tablets or oral suspension may be taken with or without food.
The recommended ZYVOXID dosage should be administered IV or orally twice daily.
Adult patients:

Infections (including those associated with concurrent bacteraemia)	Twice daily dosage and route of administration	Duration of treatment
Community-acquired pneumonia, including concurrent bacteraemia	600 mg IV or orally	10-14 consecutive days
Nosocomial pneumonia, including concurrent bacteraemia	600 mg IV or orally	10-14 consecutive days
Skin and soft tissue infections, including concurrent bacteraemia	400 mg to 600 mg orally or 600 mg IV depending on clinical severity	10-14 consecutive days
Enterococcal infections, including vancomycin-resistant infections, and those with concurrent bacteraemia	600 mg IV or orall	14-28 consecutive days

Elderly patients: No dose adjustment is necessary.

Patients with impaired renal function: There is no evidence of parent linezolid accumulation in patients with any degree of renal insufficiency.

Patients with mild to moderate renal insufficiency i.e. CLCR (creatinine clearance) >30 mL/min: No dose adjustment is required.

Patients with severe renal insufficiency i.e. CLCR <30 mL/min: Dosage should not be reduced in these patients. However, there is evidence that the primary metabolites of linezolid accumulate in patients with severe renal insufficiency. The clinical significance of this has not been established.

Linezolid should be administered after haemodialysis in patients receiving such treatment.

Patients with impaired hepatic function: No dose adjustment is necessary.

Instructions for use/handling:
Intravenous administration:
ZYVOXID Solution for Infusion must be used immediately after the seal is first broken. ZYVOXID Solution for Infusion is supplied in single-use, 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.
Administer ZYVOXID Solution for Infusion over a period of 30 to 120 minutes. Do not use the intravenous infusion bag in series connections. Do not introduce additives into the intravenous solution. If ZYVOXID Solution for Infusion 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.
Compatible infusion solutions: 0,9% Sodium Chloride Injection, 5% Dextrose Injection, Lactated Ringer’s Injection.
ZYVOXID Solution for Infusion is known to be physically incompatible with the following drugs: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isethionate, phenytoin sodium, erythromycin lactobionate and trimethoprim-sulfamethoxazole.
ZYVOXID Solution for Infusion was chemically incompatible when combined with ceftriaxone sodium.
Constitution of oral suspension:
ZYVOXID Granules for Suspension is supplied as a powder/granule for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid.
Before using the constituted suspension, gently mix by inverting the bottle several times. Do not shake.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Approximately 22% of patients experienced adverse reactions. Those most commonly reported were headache, diarrhoea, nausea, vomiting, metallic taste, abnormal liver function tests and vaginal moniliasis.
Adverse drug events occurring at frequencies greater than 0,1% include:
(Common: = 1/100 and <1/10 or = 1% and <10%
Uncommon: = 1/1 000 and < 1/100 or = 0,1% and < 1%)
General body:
Common: headache, moniliasis or fungal infection
Uncommon: chills, fatigue, fever, injection site pain, phlebitis/thrombophlebitis, localised pain
Blood and the lymphatic system disorders:
Uncommon: anaemia, eosinophilia, leucopenia, neutropenia, thrombocytopenia
Metabolism and nutrition disorders:
Uncommon: increased serum creatine phosphokinase, hyperglycaemia
Nervous system disorders:
Uncommon: dizziness, hypoaesthesia, insomnia, paraesthesia
Special senses:
Common: metallic taste
Uncommon: blurred vision, tinnitus
Cardiovascular disorders:
Uncommon: hypertension, hypotension
Gastro-intestinal disorders:
Common: abdominal pain, cramps or distension, diarrhoea, nausea, vomiting
Uncommon: constipation, dry mouth, dyspepsia, gastritis, increased thirst, pancreatitis, stomatitis, tongue discolouration or disorder
Skin disorders:
Uncommon: dermatitis, sweating, pruritus, rash, urticaria
Urogenital disorders:
Common: vaginal moniliasis
Uncommon: vulvovaginal disorder, polyuria, vaginitis
Laboratory abnormalities: Chemistry
Common: increased total bilirubin, AST, ALT, LDH, alkaline phosphatase, BUN, creatine kinase, lipase, amylase or non-fasting glucose, decreased total protein, albumin, sodium, calcium, increased or decreased potassium or bicarbonate
Uncommon: increased creatinine, sodium, calcium; decreased non-fasting glucose, increased or decreased chloride
Laboratory abnormalities: Haematology
Common: increased neutrophils or eosinophils, decreased haemoglobin, haematocrit or red blood cell count, increased or decreased platelet or white blood cell counts
Uncommon: increased reticulocyte count; decreased neutrophils
Effects on ability to drive and use machines:
No effects on the ability to drive and use machines have been observed.
Drug interactions:
Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not induce or inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with ZYVOXID without changes in dosage regimen.
No interactions have been observed in pharmacokinetic studies with either aztreonam or gentamicin.

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Clinical studies have shown that it produces a mild, reversible enhancement of the pressor responses induced by pseudoephedrine and phenylpropanolamine hydrochloride. Thus, the potential for interaction with sympathomimetic or adrenergic agents should be considered and doses of compounds, such as dopamine or adrenalin, should be titrated to achieve the desired response.

No significant pressor response was observed in subjects receiving both linezolid and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting large amounts of food and beverages with a high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).
Although linezolid has the potential for interaction with serotonergic agents, no serotonin effects (e.g. confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) were observed in subjects receiving linezolid and dextromethorphan.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No cases of overdose have been reported. However, the following information may prove useful:
Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion.

IDENTIFICATION:
ZYVOXID 400 mg Tablets: A white to off-white, ovaloid tablet, imprinted on one side with red ink “ZYVOXID 400 mg”.
ZYVOXID 600 mg Tablets: A white to off-white, ovaloid tablet, imprinted on one side with red ink “ZYVOXID 600 mg”.
ZYVOXID Solution for Infusion: A ready-to-use infusion bag containing a clear, colourless to yellow solution free of visible particles.
ZYVOXID Granules for Suspension: A white to off-white orange-flavoured granule/powder. The constituted suspension appears as a white to off-white suspension.

PRESENTATION:
ZYVOXID 400 mg Tablets: White HDPE bottles of 10 or 30 tablets or PVC/foil blisters of 10 or 30 tablets.
ZYVOXID 600 mg Tablets: White HDPE bottles of 10 or 30 tablets or PVC/foil blisters of 10 or 30 tablets.
ZYVOXID 200 mg/100 mL (solution for infusion): Single-use infusion bags packaged in a foil overwrap available in a pack size of 100 mL (200 mg linezolid).
ZYVOXID 600 mg/300 mL (solution for infusion): Single-use infusion bags packaged in a foil overwrap available in a pack size of 300 mL (600 mg linezolid).
ZYVOXID Granules for Suspension: Granules for suspension in 240 mL amber glass bottles. Once constituted, the volume of suspension is 150 mL.

STORAGE INSTRUCTIONS:
Tablets: Store at room temperature below 25°C. Tablets packed in HDPE bottles must be stored in a dry place and protected from light.
Infusion: Store at room temperature below 25°C. Infusion bags must be kept in overwrap until ready to use. Protect from light. Single-use infusion bags. Do not freeze. Discard any unused solution.
Granules for Suspension: Store at room temperature below 25°C.
Constituted Suspension: Store at room temperature below 25°C and use within 21 days.

REGISTRATION NUMBERS:
ZYVOXID 400 mg Tablets: 35/20.1.1/0309
ZYVOXID 600 mg Tablets: 35/20.1.1/0310
ZYVOXID 20 mg/mL Granules for Suspension: 35/20.1.1/0311
ZYVOXID 200 mg/100 mL Solution for Infusion: 35/20.1.1/0312
ZYVOXID 600 mg/300 mL Solution for Infusion: 35/20.1.1/0313

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George Street
Midrand 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
29 May 2001

New addition to this site: January 2005
Source: Pharmaceutical Industry
SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2005