Consumer medicine information

Zyvox

Linezolid

BRAND INFORMATION

Brand name

Zyvox

Active ingredient

Linezolid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zyvox.

What is in this leaflet

Please read this leaflet carefully before taking Zyvox. This leaflet answers some common questions about Zyvox. It does not contain all the available information. It does not take the place of talking to your or your child's doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child taking Zyvox against the expected benefits it will have.

Ask the doctor if you have any concerns about you or your child taking this medicine.

Keep this leaflet even after your treatment with Zyvox is finished. You may need to read it again.

What Zyvox is used for

Zyvox contains the active ingredient, linezolid.

Zyvox is an antibiotic (an agent used to destroy certain types of bacteria). It is used in the treatment of bacterial infections such as pneumonia, skin infections or blood infections.

Depending on the type of bacteria, you may be given additional medicines.

Your doctor, however, may prescribe Zyvox for another purpose.

Ask your doctor if you have any questions about why Zyvox has been prescribed for you or your child.

This medicine is not addictive.

Before treatment with Zyvox

When Zyvox must not be used

Zyvox must not be given if you or your child:

  • are allergic to linezolid or any of the other ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.
  • have uncontrolled high blood pressure
  • have pheochromocytoma (a type of tumour of the adrenal gland)
  • have thyrotoxicosis (an overactive thyroid gland)
  • have flushing or other symptoms caused by a carcinoid tumour
  • are taking or have taken in the last two weeks any medicine that is a monoamine oxidase inhibitor (e.g., moclobemide, phenelzine or tranylcypromine to treat depression or selegiline to treat Parkinson's disease)
  • any cold or flu medicine containing pseudoephedrine
  • adrenaline, a medicine used to treat severe allergic reactions
  • any other medicine that increases blood pressure (e.g., noradrenaline, dopamine, dobutamine)
  • are taking any medicine that is an SSRI or serotonin re-uptake inhibitor, which are types of medicine to treat depression, anxiety, panic attacks, obsessive-compulsive disorders or obesity (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, sibutramine, venlafaxine)
  • tricyclic antidepressants, which are medicines to treat depression (e.g., amitriptyline, clomipramine, dothiepin, doxepin, imipramine, nortriptyline, trimipramine)
  • some medicines to treat migraine (e.g., naratriptan, sumatriptan, zolmitriptan)
  • pethidine, a medicine to treat pain.
  • buspirone, a medicine to treat anxiety.

Do not use Zyvox if the packaging is torn or shows signs of tampering.

Do not use Zyvox after the expiry date printed on the pack has passed.

Do not use Zyvox oral suspension if it is more than 3 weeks since you received it from the pharmacist.

Before treatment with Zyvox

Tell the doctor if you or your child:

  • have diarrhoea
  • have allergies to any other medicines or substances, such as foods, preservatives or dyes
  • have phenylketonuria
    Zyvox oral suspension contains aspartame and this is partly converted into phenylalanine.
  • are anaemic or have had any abnormal blood test results (e.g., low haemoglobin or platelets)
  • are diabetic
    Zyvox injection contains glucose.

Tell the doctor if you:

  • are pregnant or planning to become pregnant
  • are breastfeeding or intend to breastfeed.

If you are pregnant or breastfeeding, the doctor may decide not to prescribe Zyvox.

Talk to the doctor or pharmacist, if you have any concerns about you or your child being given Zyvox.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

In particular, tell the doctor if you or your child have been treated with or are taking:

  • any medicine that inhibits monoamine oxidase (e.g., moclobemide, phenelzine or tranylcypromine to treat depression or selegiline to treat Parkinson's disease)
  • any cold or flu medicine containing pseudoephedrine
  • adrenaline, a medicine used to treat severe allergic reactions
  • any other medicine that increases blood pressure (e.g., noradrenaline, dopamine, dobutamine)
  • are taking any medicine that is an SSRI or serotonin re-uptake inhibitor, which are types of medicine to treat depression, anxiety, panic attacks, obsessive-compulsive disorders or obesity (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, sibutramine, venlafaxine)
  • tricyclic antidepressants, which are medicines to treat depression (e.g., amitriptyline, clomipramine, dothiepin, doxepin, imipramine, nortriptyline, trimipramine)
  • some medicines to treat migraine (e.g., naratriptan, sumatriptan, zolmitriptan)
  • pethidine, a medicine to treat pain.
  • buspirone, a medicine to treat anxiety
  • rifampicin, a medicine to treat tuberculosis and some other infections
  • any medicine that could reduce the levels of haemoglobin (the pigment in red blood cells which carries oxygen) or platelets (blood cells which help blood to clot)

Ask the doctor or pharmacist if you are not sure about this list of medicines.

Also tell the doctor if your or your child's diet contains a lot of mature cheese, yeast extracts, meat extracts, soya bean extracts (e.g., soy sauce), draught beers or wine. Zyvox may react with a substance which is naturally present in these foods.

How Zyvox is given

It is recommended that treatment with Zyvox begin in a hospital.

Tablets and Oral Suspension

Follow all directions given by your or your child's doctor carefully. These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask the doctor or pharmacist for help.

Gently mix Zyvox oral suspension by slowly turning the bottle over a few times before you use it. DO NOT SHAKE THE BOTTLE.

Do not take or give Zyvox oral suspension to your child if it is more than 3 weeks since you received it from your pharmacist.

Injection

Zyvox injection will be given to you or your child by the doctor or nurse.

Zyvox is a liquid which is given by slow injection into the blood (known as an intravenous infusion or "drip").

If you or your child is on dialysis, Zyvox infusion should be given after dialysis.

You or your child may be changed from Zyvox injection to Zyvox tablets or Zyvox oral suspension) to complete your course of treatment.

When to take it

Zyvox can be taken before, during or after meals.

If you or your child is on dialysis, take Zyvox after dialysis.

How much is given

Tablets
The recommended dose for adults and adolescents 12 years and older is one 600 mg tablet twice daily (every 12 hours).

Oral suspension
The recommended dose for babies and children up to 12 years of age is 10 mg/kg three times daily (every 8 hours).

The recommended dose for adults and adolescents 12 years and older is 30 mL (600 mg) twice daily.

Continue taking Zyvox until you or your child finish the tablets or oral suspension unless your doctor recommends otherwise.

Do not stop taking Zyvox unless your doctor tells you to, even if you feel better.

Do not stop giving Zyvox to your child unless your child's doctor tells you to, even if your child feels better. If you or your child do not complete the full course prescribed by the doctor, the bacteria causing the infection may continue to grow and multiply. The infection may not clear completely or it may return.

A course of treatment usually lasts 10 to 14 days but may be up to 28 days.

Injection
The recommended dose for adults and adolescents 12 years and older is 600 mg twice daily (every 12 hours).

The recommended doses for babies and children up to 12 years of age is 10 mg/kg three times daily (every 8 hours).

These doses are given intravenously by a "drip" over a period of 30 to 120 minutes.

Treatment is usually given every day for 10 to 14 days but may given for up to 28 days.

Ask the doctor if you want more information about the dose of Zyvox and how it is given.

In case of overdose

Immediately telephone your doctor or pharmacist or Poisons Information Centre on 13 11 26 or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have been given too much Zyvox.

Do this even if there are no signs of discomfort or poisoning. You or your child may need urgent medical attention.

Keep the telephone numbers for these places handy.

The possible effects of overdose are vomiting, tremors (shaking), unsteadiness or lack of coordination.

While being treated with Zyvox

Things you must do

Follow all instructions given by the doctor.

In some cases, additional blood tests may be required.

If the symptoms of the infection do not improve within a few days, or if they become worse, tell your or your child's doctor.

As part of the treatment, you or your child may be given other medicines including other antibiotics. It is important to keep taking these medicines as well as Zyvox unless you are told otherwise by your doctor or pharmacist.

It is important to tell the doctor if you develop diarrhoea during or after treatment with Zyvox. Do this even if it occurs several weeks after Zyvox has been stopped.

Do not take any medicine to treat diarrhoea without first checking with the doctor. Diarrhoea may be caused by a serious condition affecting the bowel. You or your child may need urgent medical care.

If you or your child get a sore white mouth or tongue during or soon after treatment with Zyvox tell your doctor.

Tell the doctor if you or your child get vaginal itching or discharge. This may mean you or your child have a fungal infection called thrush. Sometimes the use of Zyvox allows fungi to grow which causes the symptoms described above. Zyvox does not work against fungi.

Tell your doctor immediately if you become pregnant while you are being treated with Zyvox.

Tell all doctors, dentists and pharmacists who are treating you or your child that you are taking Zyvox.

Things you must not do

Do not start taking any other medicines, prescription or not, without first telling your doctor or pharmacist.

Do not give your child any other medicines, prescription or purchased from a health food shop, pharmacy or supermarket without first telling your doctor or pharmacist.

Do not take any medicine to treat diarrhoea without first checking with the doctor. Diarrhoea may be caused by a serious condition affecting the bowel. You or your child may need urgent medical care.

Avoid eating too much mature cheese, yeast extracts, meat extracts or soya bean extracts (e.g., soy sauce). Avoid drinking alcohol, especially draught beers and wine. This is because Zyvox may react with a substance which is naturally present in these foods.

If you or your child develop a throbbing headache after eating, tell your doctor or health care professional.

Do not give Zyvox to anyone else, even if they seem to have the same condition as you.

Do not take Zyvox to treat other complaints unless your doctor tells you to do so.

Side effects

Tell the doctor or pharmacist as soon as possible if you or you child do not feel well while you are being treated with Zyvox.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by the following lists of side effects. You or your child may not experience any of them.

Ask the doctor or pharmacist to answer any questions you may have.

Tell the doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • sore, white mouth or tongue (oral thrush)
  • vaginal itching or discharge (vaginal thrush)
  • pain, cramping or bloating of the abdomen
  • nausea or vomiting
  • metallic taste
  • change in the colour of the tongue
  • change in the colour of teeth. This may be reversible.

Tell your doctor immediately and before you or your child are given the next dose of Zyvox if you notice any of the following:

  • skin reactions (hives, rash or itching)
  • visual disturbances or numbness or weakness of the arms and legs (rare side effects that have been primarily reported in patients treated for longer than 28 days)
  • tiredness, headaches, being short of breath when exercising, dizziness, looking pale, dark circles around the eyes, fever and chills, sore throat or bruising (these symptoms may indicate a decrease in the level of your blood cells)
  • sweating, feeling drunk and dizzy, muscle twitching, fever and shivering, confusion
    These may be symptoms of the serotonin syndrome, which is a rare but serious side effect.

If any of the following happen, tell your or your child's doctor immediately or go to Accident and Emergency at your nearest hospital:

  • seizure
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, severe itching or hives or blisters on the skin and bleeding in the lips, eyes, mouth, nose and genitals.
  • widespread painful red areas, followed by blisters and ends with peeling of layers pf skin. This may be accompanied by fevers and chills, aching muscles and generally feeling unwell.

These may be signs of a serious allergic reaction or side effect. You or your child may need urgent medical attention or hospitalisation. These side effects are rare.

After stopping your treatment

Tell your or your child's doctor or pharmacist if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with Zyvox:

  • severe stomach cramps
  • watery and severe diarrhoea (which may be bloody), fever, in combination with one or both of the above.

Zyvox can cause some bacteria, which are normally present in the bowel and normally harmless, to multiply and therefore cause the above symptoms. You may need urgent medical attention.

Tell your or your child's doctor if you notice any other side effects. Other side effects not listed above may also occur in some people.

After using Zyvox

Storage

Keep Zyvox tablets and Zyvox oral suspension in a cool dry place where the temperature stays below 25°C.

Keep your tablets or oral suspension in the original packaging, including outer carton, until it is time to take them. Keep oral suspension bottles tightly closed. If you take the medicine out of the pack it may not keep well.

Do not store Zyvox or any other medicines in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Zyvox where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Zyvox injection will normally be stored in a hospital. It should be stored below 25°C and should be protected from light (kept in the box and foil wrapping before use).

Hospital staff will make sure the medicine is not used after the expiry date printed on the bag.

Product description

What Zyvox looks like

Zyvox tablets are white to off-white coated tablet with "ZYV" debossed on one side and "600" debossed on the other. The tablets are available in blister packs of 10 tablets.

Zyvox oral suspension is a white to yellow-orange fluid which is orange flavoured. It is supplied in an amber glass bottle with a screw cap. A measuring spoon with 2.5 mL and 5 mL markings is also provided.

Zyvox injection is a sterile, clear, colourless to yellow fluid for injection supplied as 300 mL in infusion bags. Each bag is for single use only and is packaged in a foil overwrap contained within an outer carton.

Ingredients

The active ingredient in Zyvox is linezolid.

Zyvox tablets contain 600 mg of linezolid.

The tablets also contain:

  • microcrystalline cellulose (E460i)
  • maize starch
  • sodium starch glycollate
  • hyprolose (E463)
  • magnesium stearate (E572).

The film coating contains:

  • hypromellose (E464)
  • titanium dioxide (E171)
  • macrogol 400
  • carnauba wax (E903).

Zyvox oral suspension contains 20 mg/mL of linezolid (total 150 mL).

Other ingredients are:

  • sucrose
  • mannitol (E421)
  • microcrystalline cellulose (E460i)
  • carmellose sodium (E466)
  • aspartame (E951)
  • colloidal anhydrous silica (E551)
  • sodium citrate dihydrate (E331)
  • xanthan gum (E415)
  • sodium benzoate (E211)
  • citric acid (E330)
  • sodium chloride.

The granules are flavoured with Mafco magnasweet, orange flavour, orange cream flavour, Sweet-am powder, vanilla flavour and peppermint flavour.

Important information about some of the ingredients in Zyvox oral suspension

This medicine contains

  • aspartame, which is partly converted into phenylalanine.
  • sodium benzoate is known to be a mild irritant to the skin, eyes and mucous membranes. In the quantities present in Zyvox suspension (0.2%) no harmful effects are expected.
  • sodium may be harmful in a low-sodium diet. Each mL contains sodium as sodium citrate dihydrate (3 mg), sodium benzoate (2 mg) and sodium chloride (2.7 mg).
  • Each mL contains 210.6 mg sucrose, 100 mg mannitol (E421) and 7 mg aspartame (E951). Fructose and sorbitol (E420) are present in mafco magna sweet (12 mg) and sweet-am powder (6 mg).

Zyvox is not suitable for treating people with hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.

Sucrose may cause gastrointestinal complaints and diarrhoea.

Zyvox injection contains 2 mg/mL of linezolid.

Other ingredients are:

  • glucose monohydrate
  • sodium citrate dihydrate (E331)
  • citric acid (E330)
  • hydrochloric acid (E507)/ sodium hydroxide (E524)
  • water for injections.

Each mL of Zyvox solution of injection contains 50.24 mg glucose monohydrate and sodium as sodium citrate dihydrate (1.64 mg).

Supplier

Zyvox is supplied by:

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free Number: 1800-675 229.
www.pfizer.com.au

Australian Registration Number

600 mg tablets: AUST R 79694

20 mg/mL oral suspension: AUST R 79695

600 mg/300 mL injection: AUST R 79690

Date of preparation

This leaflet was revised in July 2020.

© Pfizer Australia Pty Ltd.

® = Registered trademark

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Zyvox

Active ingredient

Linezolid

Schedule

S4

 

1 Name of Medicine

Linezolid.

2 Qualitative and Quantitative Composition

Tablets.

Each Zyvox tablet contain 600 mg linezolid.

Granules for oral suspension.

Following reconstitution with 123 mL of water, each mL contains 20 mg of linezolid.

Solution for injection.

Each 1 mL of Zyvox solution for injection (Zyvox injection) contains 2 mg of linezolid.

Excipient(s) with known effect.

Granules for oral suspension.

Each mL contains 210.6 mg sucrose, 100 mg mannitol (E421) and 7 mg aspartame (E951), sodium as sodium citrate dihydrate (3 mg), sodium benzoate (2 mg) and sodium chloride (2.7 mg). Fructose and sorbitol (E420) are present in mafco magna sweet (12 mg) and sweet-am powder (6 mg).

Solution for injection.

Each mL contains 50.24 mg glucose monohydrate and sodium as sodium citrate dihydrate (1.64 mg).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Zyvox 600 mg tablets are white to off-white coated tablet with "ZYV" debossed on one side and "600" debossed on the other.

Granules for oral suspension.

Zyvox granules for oral suspension are white to yellow-orange and may contain white to yellow-orange-brown lumps. The constituted suspension is white to yellow-orange and orange flavoured.

Solution for injection.

Zyvox injection is in an isotonic, clear, colourless to yellow solution with pH between 4.4-5.2.

4 Clinical Particulars

4.1 Therapeutic Indications

Zyvox is indicated for the treatment of suspected or proven infections due to Gram positive organisms resistant to multiple classes of antibiotics, including methicillin resistant Staphylococcus species and vancomycin resistant Enterococcus species.
Zyvox is active against Gram positive bacteria only. Zyvox has no clinical activity against Gram negative pathogens. Specific Gram negative therapy is required if a concomitant Gram negative pathogen is documented or suspected.

4.2 Dose and Method of Administration

Dosage.

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 Zyvox has an oral bioavailability of approximately 100%.
The injection should be administered over a period of 30 to 120 minutes. The maximum recommended duration of treatment is 28 days. Serious adverse effects have been associated with treatment prolonged beyond 28 days. See Section 4.4 Special Warnings and Precautions for Use, Myelosuppression, Peripheral neuropathy and optic neuropathy.

Adults and children 12 years or older.

The recommended dosage should be administered intravenously or orally (twice daily) bid as shown in Table 1. Duration of treatment is variable. It is dependent on the pathogen, the site of infection and its severity, and on the patient's clinical response. The maximum recommended duration of treatment is 28 days. No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia.

Children less than 12 years old.

The recommended dosage should be administered intravenously or orally as shown in Table 2. The maximum recommended duration of treatment is 28 days.

Method of administration.

Tablets and granules for oral suspension.

Administered orally with or without food.

Granules for oral suspension.

Instructions for use and handling.

Keep the bottle tightly closed before reconstitution.
The granules should be reconstituted using 123 mL of water in two approximately equal aliquots to produce 150 mL oral suspension. Shake well to obtain a uniform suspension. Keep the bottle in the outer carton after reconstitution.
Before use, gently mix by inverting the bottle several times. Do not shake. Discard if not used within 3 weeks after reconstitution.

Solution for injection.

Instructions for use and handling.

Keep bags in foil overwrap and carton until ready to use. Remove overwrap then check for minute leaks by squeezing the bag firmly. Do not use if the bag leaks as sterility may be impaired.
Zyvox injection contains no preservative. The product is for single use in one patient only. Discard any residue. Do not use the bags in series connections. Do not reconnect partially used bags.
Any solutions which are discoloured, hazy or contain visible particulate matter should not be used.

Dosage adjustment.

No dose adjustment is required in the elderly, in patients with impaired hepatic function or impaired renal function. However, Zyvox should be administered after haemodialysis in patients receiving such treatment (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to linezolid or to any of the excipients in the relevant pharmaceutical form (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients).

Monoamine oxidase inhibitors.

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine) 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. adrenaline (epinephrine), noradrenaline (norepinephrine)), dopaminergic agents (e.g. dopamine, dobutamine) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 reuptake inhibitors, tricyclic antidepressants, serotonin 5HT1-receptor agonists (triptans), pethidine or buspirone (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

It is recommended that therapy with Zyvox should be initiated in a hospital environment following guidance from appropriate specialists.

Myelosuppression.

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

Peripheral neuropathy and optic neuropathy.

Peripheral neuropathy and optic neuropathy have been reported in patients treated with linezolid, primarily those patients treated for longer than the maximum recommended duration of 28 days. When outcome was known, recovery was reported in some cases following Zyvox withdrawal. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration.
If symptoms of visual impairment appear, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods (greater than or equal to 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks.
The safety and effectiveness of Zyvox when administered for periods longer than 28 days have not been established. Treatment prolonged beyond 28 days has been associated with serious adverse effects, including myelosuppression, peripheral neuropathy and optic neuropathy.

Lactic acidosis.

Lactic acidosis has been reported with the use of linezolid. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should receive immediate medical attention.

Convulsions.

Convulsions have been reported to occur rarely in patients when treated with linezolid. In most of these cases, a history of seizures or risk factors for seizures were reported.

Serotonin syndrome.

Spontaneous reports of serotonin syndrome associated with the coadministration of Zyvox and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Antibiotic associated pseudomembranous colitis.

Antibiotic associated pseudomembranous colitis has been reported with nearly all antibacterial agents including linezolid. A toxin produced with Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine, may prolong and/or worsen the condition and should not be used. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

Superinfection.

The use of antibiotics may occasionally result in an overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
Linezolid has no clinical activity against Gram negative pathogens and is not indicated for the treatment of Gram negative infections. Specific Gram negative therapy is required if a concomitant Gram negative pathogen is documented or suspected. Linezolid should be used with special caution in patients at high risk of life threatening systemic infections, such as those with infections related to central venous catheters in intensive care units. Linezolid is not approved for the treatment of patients with catheter related bloodstream infections.

Mortality in subjects with catheter related infections.

An open label, randomised clinical trial was conducted in adult patients with catheter related Gram positive bloodstream infections comparing linezolid (600 mg q12h IV/PO) to vancomycin 1 g IV q12h or oxacillin 2 g IV q6h/dicloxacillin 500 mg PO q6h with a treatment duration of 7 to 28 days. The mortality rates in this study were 78/363 (21.5%) and 58/363 (16.0%) on linezolid and the comparator, respectively. Based on results from a logistic regression, the estimated odds ratio is 1.426 [95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid treated patients in whom either Gram negative pathogens, mixed Gram negative and Gram positive pathogens, or no pathogens were identified at baseline. Patients randomised to linezolid who had only a Gram positive infection at baseline, including the subgroup of patients with Gram positive bacteraemia experienced a survival rate similar to the comparator.

Use in the elderly.

The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and over. No dose adjustment is required.

Paediatric use.

The clearance of linezolid is most rapid in the youngest age groups (excluding neonates less than 1 week old), resulting in a shorter half-life. As children mature, the clearance of linezolid gradually decreases and by adolescence the clearance values approach those observed for the adult population. While drug clearance in adolescents (ages 12 through 17 years) is usually similar to the clearance in adults, there is wider intersubject variation in this age group compared with adults (see Section 5.2 Pharmacokinetic Properties, Special populations, Children and adolescents). Results of clinical studies showed similar efficacy in adult and adolescent patients. Given the wider intersubject variation in adolescents, the slight possibility that high clearance may result in decreased efficacy in some adolescent patients should be considered. The dosage for pediatric patients younger than 12 years of age should be 10 mg/kg every 8 hours, while children 12 years and older should receive the same dose as adult patients, 600 mg every 12 hours (see Section 4.2 Dose and Method of Administration).
In limited clinical experience, 5 out of 6 (83%) paediatric patients with infections due to Gram positive pathogens with MICs of 4 microgram/mL treated with Zyvox had clinical cures. However, paediatric patients with a suboptimal clinical response, particularly those with pathogens with MIC of 4 microgram/mL, lower systemic exposure, site and severity of infection and the underlying medical condition should be considered when assessing clinical response (see Section 5.1 Pharmacodynamic Properties, Paediatric patients; Section 4.2 Dose and Method of Administration).

Renal impairment.

Linezolid should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk.

Hepatic impairment.

It is recommended that linezolid should be used in patients with severe hepatic insufficiency only when the anticipated benefit is considered to outweigh the theoretical risk.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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 with Zyvox. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with Zyvox without changes in dosage regimen.
Zyvox is a reversible, nonselective inhibitor of monoamine oxidase (MAOI). Limited clinical studies have shown that coadministration of Zyvox with either pseudoephedrine or phenylpropanolamine resulted in mild, reversible enhancement of the pressor responses in normotensive patients. Similar studies in hypertensive subjects have not been conducted. The potential for interaction with sympathomimetic and adrenergic agents should be considered (see Section 4.3 Contraindications). Initial doses of potent vasopressors, such as dopamine and adrenaline (epinephrine), should be reduced and carefully titrated to achieve the desired response when coadministered with Zyvox (see Section 4.3 Contraindications).
No significant pressor response was observed in subjects receiving both Zyvox and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting excessive 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).
Zyvox has the potential for interaction with serotonergic agents. Limited clinical studies have shown that coadministration of Zyvox with dextromethorphan was not associated with serotonin syndrome effects (e.g. confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia). The effects of other serotonin uptake inhibitors have not been studied.
Spontaneous reports of serotonin syndrome associated with coadministration of Zyvox and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported (see Section 4.3 Contraindications). Patients who are treated with Zyvox and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome (e.g. cognitive dysfunction, hyperpyrexia, hyperreflexia, incoordination). If any signs or symptoms occur physicians should consider discontinuation of either one or both agents (Zyvox or concomitant serotonergic agents). If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed.

Antibiotics.

No interactions have been observed in pharmacokinetic studies with either aztreonam or gentamicin.
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg bid for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin decreased the linezolid Cmax and AUC by a mean 21% (90% CI 15, 27) and a mean 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Whilst linezolid did not affect female rat fertility or reproductive performance, it reversibly decreased the fertility of adult male rats at oral doses of 50 mg/kg/day with exposure levels (based on AUC) approximately equal to those expected in humans. The reversible effects on fertility were mediated by altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were nonviable. The presence of abnormal sperm in the epididymis was accompanied by epithelial cell hypertrophy and hyperplasia.
Dogs administered linezolid at PO doses up to 40 mg/kg/day (0.7 times clinical exposure) for 3 months or IV doses up to 40 mg/kg/day (1.3 times clinical exposure) for 1 month showed no effects on the testes or epididymides.
Sexually mature male rats showed slightly decreased fertility following oral treatment as juveniles throughout most of their period of sexual development (50 mg/kg/day from postnatal days 7 to 36, and 100 mg/kg/day from days 37 to 55), at exposures up to 1.7 times the mean AUC in paediatric patients aged 3 months to 11 years. Decreased fertility was not observed following a shorter treatment period of about 2 weeks, in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats following treatment on postnatal days 22 to 35.
Juvenile dogs administered linezolid for 1 month at doses up to 100 mg/kg/day PO (2.2 times clinical paediatric exposure) showed no direct effects on the testes or epididymides.
(Category B3)
There are no adequate data from the use of Zyvox in pregnant women. Studies in animals have shown reproductive effects (see below). The potential risk for humans is unknown.
Zyvox should not be used during pregnancy unless clearly necessary, i.e. only if the potential benefit outweighs the potential risk.
Linezolid and/or its metabolites crossed the placenta in rats. Linezolid was not teratogenic in mice or rats at exposure levels 4 times (mice) or equivalent to (rats) the expected human exposure level, based on AUCs.
Embryofetal effects were observed in mice at 450 mg/kg/day (4 times the clinical exposure based on AUC) and in rats at 15 mg/kg/day (0.14 times the clinical exposure based on AUC). Decreased fetal weights and delayed ossification occurred in rats without maternal toxicity. In mice, increased embryo death including total litter loss, decreased fetal bodyweights and an exacerbation of the normal genetic predisposition to sternal variations in the strain of mice used were seen at doses causing maternal toxicity (clinical signs and decreased bodyweight gain).
Linezolid was also not teratogenic in rabbits, when administered bid at total oral doses up to 15 mg/kg/day (0.06 times the clinical exposure, based on AUC), although maternal toxicity (clinical signs, reduced bodyweight gain and food consumption) occurred at 5 and 15 mg/kg/day and reduced fetal bodyweight occurred at 15 mg/kg/day. Linezolid exposures were low due to the characteristic sensitivity of rabbits to antibiotics.
Animal data suggest that linezolid is likely to pass into breast milk. Breastfeeding should be discontinued prior to administration.
Linezolid and its metabolites were excreted into the milk of rats. The concentration of total drug related materials in milk was similar to or greater than that in maternal plasma. The development of pups from rats treated orally with 50 mg/kg/day linezolid during gestation and lactation (0.6 times the clinical exposure based on AUC) was slightly delayed, manifest as decreased bodyweight gain, delayed pinna detachment and balanopreputial separation and decreased negative geotaxis response. These pups when allowed to mature, showed slightly decreased fertility, increased implantation loss and decreased epididymides and testes weights.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned about the potential for dizziness or symptoms of visual impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)) whilst receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occurs.

4.8 Adverse Effects (Undesirable Effects)

The information provided is based on data generated from clinical studies in adult and paediatric patients.

Adult patients.

More than 2,000 patients received the recommended Zyvox doses for up to 28 days. In these studies, the majority of adverse reactions to Zyvox were of mild to moderate intensity, of limited duration and did not require discontinuation of treatment. The adverse reactions were not dose dependent.
Approximately 22% of patients experienced adverse reactions; those most commonly reported were headache, diarrhoea, nausea, vomiting, taste perversion, abnormal liver function tests and candidiasis (particularly oral and vaginal). The most commonly reported drug related adverse events which lead to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. Table 3 shows the incidence of adverse reactions reported in at least 1% of patients in these trials.
Changes observed in laboratory parameters (without regard to drug relationship) generally reflected resolution of the infection, were not clinically significant, did not lead to discontinuation of therapy and were reversible. The incidence of patients with at least one substantially abnormal haematologic or serum chemistry value is presented in Table 4.

Paediatric patients.

The safety of Zyvox formulations was evaluated in 215 paediatric patients ranging in age from birth through 11 years and in 248 paediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two phase 3 comparator controlled clinical trials and were treated for up to 28 days. In these studies 83% and 99% respectively, of the adverse events reported with Zyvox were described as mild to moderate in intensity. In the study of hospitalised paediatric patients (birth through 11 years) with Gram positive infections, who were randomised 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 5 shows the incidence of drug related adverse events reported in more than 1% of paediatric patients (and more than 1 patient) in either treatment group in the comparator controlled phase 3 trials.
In a study of severely ill, hospitalised paediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count was 12.9% with Zyvox and 13.4% with vancomycin. In an outpatient study of paediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with Zyvox and 0.4% with cefadroxil. Other changes observed in laboratory parameters, were not clinically significant, did not lead to discontinuation of therapy and were reversible. The incidence of paediatric patients with at least one substantially abnormal haematologic or serum chemistry value is presented in Table 6.

Post-marketing experience.

Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) and sideroblastic anaemia have been reported.
Peripheral neuropathy and optic neuropathy, sometimes progressing to loss of vision, have been reported in patients treated with linezolid. These reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days (see Section 4.4 Special Warnings and Precautions for Use). Lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use), rash, convulsions, angioedema and anaphylaxis have been reported. Very rare reports of bullous skin disorders including severe cutaneous adverse reactions such as those described as as toxic epidermal necrolysis and Stevens Johnson syndrome have been received.
Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and Zyvox (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Tongue discoloration. Superficial tooth discoloration has been reported very rarely with the use of linezolid. The discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Abdominal pain, abdominal cramps and abdominal distension have reported and considered drug-related in controlled clinical trials.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific antidote is known.
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. The two primary metabolites of linezolid are also removed to some extent by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 for advice on the management of an overdose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Linezolid is a synthetic, antibacterial agent belonging to a class of antibiotics, the oxazolidinones, with in vitro activity against Gram positive aerobic bacteria, some Gram positive anaerobic bacteria and certain Gram negative bacteria. It selectively inhibits bacterial protein synthesis via a mechanism of action different from that of other antibacterial agents. Linezolid binds to the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome 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.

Breakpoints.

The Minimum Inhibitory Concentration (MIC) breakpoints in Table 7 separate susceptible from nonsusceptible isolates.
The studies used to define the above breakpoints employed standard NCCLS (National Committee for Clinical Laboratory Standards) microdilution and agar diffusion methods.

Susceptibility.

Prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. Therefore, the following information gives only an approximate guidance on the probabilities as to whether or not microorganisms will be susceptible to linezolid. Only microorganisms relevant to the given clinical indications are presented here. An asterisk indicates that clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

Susceptible organisms.

Gram positive aerobes: Corynebacterium jeikeium, Enterococcus faecalis (including glycopeptide resistant strains), Enterococcus faecium (including glycopeptide resistant strains), Enterococcus casseliflavus, Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus (including methicillin resistant strains), Staphylococcus aureus (including glycopeptide intermediate resistant 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, Viridans group streptococci, Group C streptococci, Group G streptococci.
Gram negative aerobes: Pasteurella canis, Pasteurella multocida.
Gram positive anaerobes: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.
Gram negative anaerobes: Bacteroides fragilis, Prevotella species.
Other: Chlamydia pneumoniae.

Intermediately susceptible organisms.

Legionella species, Moraxella catarrhalis.

Resistant organisms.

Haemophilus influenzae, Neisseria species, Enterobacteriaceae, Pseudomonas aeruginosa.

Resistance.

The mechanism of action of linezolid differs from other classes of antibiotics. Cross resistance between linezolid and other classes of antibiotics is thus less likely to occur.
Resistance to linezolid developed under selective pressure. The presence of multiple 23S ribosomal RNA genes in most species suggest that the level of resistance is associated with the number of copies with mutations. Spontaneous resistance occurs at frequencies of less than 10-9 in vitro. These same mutations and/or other genetic changes have been reported in clinical isolates of Staphylococcus aureus, Streptococcus pneumoniae and Enterococci resistant or nonsusceptible to linezolid. In clinical trials, resistance to linezolid developed in 6 patients infected with E. faecium (4 patients received 200 mg twice daily (bid), lower than the recommended dose, and 2 patients received 600 mg bid. In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with E. faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. In cases where linezolid nonsusceptible enterococci are identified, strict infection control measures and adherence to antibiotic guidelines should be maintained.

Clinical trials.

There are no data from comparator controlled clinical trials on the use of Zyvox in the treatment of endocarditis, central nervous system infections and osteomyelitis.

Nosocomial pneumonia.

Adult patients with clinically and radiologically documented nosocomial pneumonia participated in a randomised, multicentre, double blind clinical trial. Patients were treated for 7 to 21 days. One group (no. enrolled = 205) received Zyvox injection 600 mg bid, and another group (no. enrolled = 197) received vancomycin 1 g bid intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours IV). Zyvox demonstrated efficacy equivalent to vancomycin in the treatment of patients with nosocomial pneumonia in all outcome measurements. The overall clinical cure rates in the ITT population was 53% in the Zyvox group and 52% in the vancomycin group. These cure rates do not include patients with missing or indeterminate outcomes. The clinical cure rate for microbiologically evaluable patients is presented in Table 8.

Community acquired pneumonia.

Adult patients with clinically and radiologically documented community acquired pneumonia participated in two randomised, comparator controlled, multicentre trials.
One of these trials was an open label study in which hospitalised patients received study medications administered IV followed by medications administered orally for a total of 7 to 14 days of treatment. One group of patients (no. enrolled = 389) received Zyvox injection (600 mg bid) followed by Zyvox tablets (600 mg bid), and another group (no. enrolled = 370) received ceftriaxone (1 g bid IV) followed by cefpodoxime proxetil tablets (200 mg bid orally).
The second study was an investigator blinded trial in outpatients with community acquired pneumonia who were treated for 10-14 days. One group of patients received Zyvox tablets 600 mg bid (no. enrolled = 278) and another group received cefpodoxime proxetil tablets 200 mg bid (no. enrolled = 270).
In these trials, Zyvox demonstrated efficacy equivalent to ceftriaxone or cefpodoxime proxetil by all outcome measurements. The overall clinical cure rates in the ITT population in Zyvox and comparator groups were 83% vs 76% and 82% vs 86% in respective studies. These cure rates do not include patients with missing or indeterminate outcomes. Table 9 shows the clinical cure rates for microbiologically evaluable patients in these studies.

Complicated skin and skin structure infections.

Adult patients with clinically documented complicated skin and skin structure infections participated in a randomised, multicentre, double blind trial comparing study medications administered IV followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients (no. enrolled = 403) received Zyvox injection (600 mg bid) followed by Zyvox tablets (600 mg bid); another group (no. enrolled = 423) received oxacillin 2 g every 6 hours (q6h) IV followed by dicloxacillin 500 mg q6h orally. Zyvox demonstrated equivalent efficacy to oxacillin and dicloxacillin against a variety of common pathogens by all outcome measurements. The overall clinical cure rates in the ITT population was 85% in the Zyvox group and 77% in the oxacillin group, respectively. These cure rates do not include patients with missing or indeterminate outcomes. The clinical cure rates for microbiologically evaluable patients are presented in Table 10.

Methicillin resistant Staphylococcus aureus (MRSA) infections.

Adult patients with documented MRSA infections participated in a randomised, multicentre, open label trial. One group of patients (no. enrolled = 243) received Zyvox injection 600 mg bid followed by Zyvox tablets 600 mg bid. Another group of patients (no. enrolled = 225) received vancomycin 1 g bid IV. Both groups were treated for 7 to 28 days. Zyvox was comparable to vancomycin in the treatment of patients with MRSA pneumonia and skin and soft tissue infections. The overall clinical cure rates in the ITT population were 57% in the Zyvox group and 55% in the comparator groups respectively. These cure rates do not include patients with missing or indeterminate outcomes. The clinical cure rates for microbiologically evaluable patients with MRSA are presented in Table 11.

Vancomycin resistant enterococcus (VRE) infections.

Adult patients with documented or suspected VRE infections participated in a randomised, multicentre, double blind trial comparing a high dose (600 mg bid IV or orally) with a low dose of linezolid (200 mg bid IV or orally) for 7 to 28 days. 79 patients were enrolled in the high dose group and 66 enrolled in the low dose group.
Patients with VRE infections were also treated with Zyvox 600 mg bid IV or orally in an open label, noncomparative, compassionate use trial. These patients were treated for up to 21 days. 144 patients with VRE infections were enrolled in this trial.
The overall clinical cure rates in the ITT populations were 67% and 54% in the high dose compared to low dose group in the controlled study, and 90% (evaluable population) in the compassionate use trial. These cure rates do not include patients with missing or indeterminate outcomes. The clinical cure rates for clinically evaluable patients are presented in Table 12 by source of infection.

Paediatric patients.

Infections due to resistant gram positive organisms.

A safety and efficacy study (study 082) provided experience on the use of Zyvox in paediatric patients for the treatment of hospital acquired pneumonia, complicated skin and skin structure infections, catheter related bacteraemia of unidentified source, and other infections due to resistant Gram positive bacterial pathogens, including methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), penicillin resistant Streptococcus pneumoniae (PRSP) and vancomycin resistant Enterococcus faecium (VRE). Paediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected above organisms were enrolled in a randomised, open label, comparator controlled trial. One group of patients received Zyvox injection 10 mg/kg every 8 hours followed by Zyvox oral suspension 10 mg/kg every 8 hours. A second group received vancomycin 10 to 15 mg/kg IV every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received Zyvox 10 mg/kg every 8 hours IV and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram negative antibiotics if clinically indicated. There were 215 linezolid treated and 101 vancomycin treated patients enrolled in the study. One hundred and fifty-one (70.2%) linezolid treated patients and 73 (72.3%) vancomycin treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 89% in linezolid treated patients and 85% in vancomycin treated patients. The cure rates for clinically and microbiologically evaluable patients are presented in Table 13.

5.2 Pharmacokinetic Properties

The mean pharmacokinetic parameters (standard deviation) of linezolid following single and multiple (i.e. twice daily administration to steady-state) intravenous (IV) and oral dosing are given in Table 14.
As can be seen from Table 14, average Cmin values achieved in plasma using the 600 mg bid dosage regimen approximate to the highest MIC90 (4 microgram/mL) for the least susceptible microorganisms.

Absorption.

Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing and the absolute bioavailability is approximately 100%. Absorption from the oral suspension is similar to that achieved with the film coated tablets. Steady-state conditions are achieved by the second or third day of dosing.
Zyvox 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 AUC(0-∞) values is similar under both conditions.

Distribution.

Linezolid is readily distributed to well perfused tissues. Its volume of distribution at steady-state averages about 40-50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31% and is not concentration dependent. 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 noninflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple linezolid dosing.

Metabolism.

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. Metabolic oxidation of the morpholine ring results primarily in two inactive open ring carboxylic acid derivatives. The hydroxyethyl glycine metabolite (A) is the predominant human metabolite and is formed by a nonenzymatic process. The amino ethoxy acetic acid metabolite (B) is less abundant. Other minor, inactive metabolites have been characterised.

Excretion.

In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted as metabolite A (40%), parent drug (30-35%) and metabolite B (10%) in the urine. Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each dose appears as metabolites A and B, respectively. The elimination half-life averages at about 5-7 hours.
Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of nonlinearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and nonrenal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.

Special populations.

Elderly (> 65 years).

The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and over.

Children and adolescents.

The pharmacokinetics of linezolid following a single IV dose were investigated in healthy adolescent subjects, ranging in age from 12 through 17 years, and in paediatric patients, ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarised in Table 15 for the paediatric populations studied and healthy adults subjects after administration of single IV dose.
The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in paediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of preterm 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 paediatric patients increases, the clearance of linezolid gradually decreases and by adolescence mean clearance values approach those observed for the adult population. There is a wider intersubject variability in linezolid clearance and systemic drug exposure (AUC) across all paediatric age groups as compared with adults.
Similar mean daily AUC values were observed in paediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for paediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Paediatric patients 12 years and older should receive 600 mg every 12 hours (see Section 4.2 Dose and Method of Administration).
Recommendations for the dosage regimen for preterm neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 preterm neonates. Most of these preterm neonates have lower systemic linezolid clearance values and larger AUC values than many full term neonates and older infants. Therefore, these preterm neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of a 10 mg/kg every 8 hours regimen in neonates with a suboptimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life (see Section 4.2 Dose and Method of Administration).

Renal impairment.

No dose adjustment is necessary in patients with either mild, moderate or severe renal insufficiency as total clearance is independent of creatinine clearance. There is evidence that the two primary metabolites of linezolid accumulate in patients with severe renal insufficiency (CLCR < 30 mL/min). The clinical significance of this has not been established as limited safety data are currently available. As approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis (beginning 3 hours after administration), Zyvox should be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid are also removed by haemodialysis, but the concentrations of these metabolites are still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid.

Hepatic impairment.

The pharmacokinetics of linezolid are not altered in patients with mild to moderate hepatic insufficiency. Dose adjustment in such patients is not required. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated. However, as linezolid is metabolised by a nonenzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.

Gender.

Some pharmacokinetic parameters of linezolid differ in female subjects. Females have a slightly lower volume of distribution than males and the mean clearance is reduced by approximately 20% when corrected for body weight. Plasma concentrations are somewhat higher in females and this can partly be attributed to body weight differences. However, because the mean half-life of linezolid is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of genotoxicity in tests for gene mutations (bacteria and Chinese hamster ovary cells), chromosomal changes (human lymphocytes in vitro and mouse micronucleus assay in vivo) and DNA damage (unscheduled DNA synthesis in vitro).

Carcinogenicity.

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets.

Microcrystalline cellulose, maize starch, sodium starch glycollate, hyprolose, magnesium stearate and in the film coating, Opadry YS-1-18202-A White and carnauba wax.

Granules for oral suspension.

Sucrose, mannitol, microcrystalline cellulose, carmellose sodium, aspartame, colloidal anhydrous silica, sodium citrate dihydrate, xanthan gum, sodium benzoate, citric acid and sodium chloride. The granules are flavoured with Mafco magnasweet, orange flavour, orange cream flavour, sweet-am powder, vanilla flavour and peppermint flavour.

Solution for injection.

Glucose monohydrate, sodium citrate dihydrate, citric acid, hydrochloric acid/sodium hydroxide and water for injections.

6.2 Incompatibilities

Additives should not be introduced into Zyvox solution for injection. If Zyvox is to be given concomitantly with other drugs, each drug should be given separately in accordance with its own directions for use. Similarly, if the same intravenous line is to be used for sequential infusion of several drugs, the line should be flushed prior to and following Zyvox administration with a compatible infusion solution (5% glucose solution for injection, 0.9% sodium chloride solution for injection or compound sodium lactate soluton for injection [Hartmann's solution for injection]).
Zyvox injection is known to be physically incompatible with the following compounds: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, phenytoin sodium and sulphamethoxazole/ trimethoprim.
Additionally, it is chemically incompatible with ceftriaxone sodium.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Granules for oral suspension.

Before reconstitution: Keep the bottle tightly closed.
After reconstitution: Keep the bottle in the outer carton in order to protect from light. Keep the bottle in the outer carton after reconstitution. Discard if not used within 3 weeks after reconstitution.

Solution for injection.

Store in the original package (overwrap and carton) until ready to use in order to protect from light.
After opening, from a microbiological point of view, the product should be used immediately. The product is for single use in one patient only. Discard any residue.

6.4 Special Precautions for Storage

Store below 25°C. Store in orginal container in order to protect from light.

6.5 Nature and Contents of Container

Tablets.

PVC/AL blister packs of 10's and 30's.

Granules for oral suspension.

Amber glass bottle with screw cap packaged in a box with a 2.5 mL/5 mL measuring spoon; 150 mL pack of 1.

Solution for injection.

Single use, ready-to-use, film infusion bags. Bags are sealed inside a foil laminate overwrap and packed in boxes of 1 or 10 100 mL, 200 mL and 300 mL infusion bags.
Not all pack sizes and presentations are supplied.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


The chemical name is (S)-N-[[3-[3-fluoro-4-(4- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl] methyl]-acetamide. The empirical formula of linezolid is C16H20FN3O4 and the molecular weight of 337.35.
The aqueous solubility of linezolid is approximately 3 mg/mL, independent of pH between pH 3 to 9.

CAS number.

165800-03-3.

7 Medicine Schedule (Poisons Standard)

S4, Prescription only medicine.

Summary Table of Changes