Consumer medicine information

Linevox

Linezolid

BRAND INFORMATION

Brand name

Linevox

Active ingredient

Linezolid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Linevox.

SUMMARY CMI

LINEVOX

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Linevox?

Linevox contains the active ingredient linezolid. It is used in the treatment of bacterial infections such as pneumonia, skin infections or blood infections. For more information, see Section 1. Why am I using Linevox? in the full CMI.

2. What should I know before I use Linevox?

Do not use if you or your child have ever had an allergic reaction to Linevox or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Linevox? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Linevox and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Linevox?

  • Your doctor will give you instruction on how to take Linevox tablets.

More instructions can be found in Section 4. How do I use Linevox? in the full CMI.

5. What should I know while using Linevox?

Things you should do
  • Tell your doctor if the symptoms of the infection do not improve within a few days, or if they become worse; you or your child have severe diarrhoea, a sore white mouth or tongue; you have vaginal itching or discharge; or if you are pregnant, or plan to become pregnant.
  • Tell any other doctor or dentist you visit that you or your child are using Linevox.
  • For more information on "Things you should do" can be found in Section 5 in the full CMI.
Things you should not do
  • Do not stop using this medicine or lower the dosage without checking with your doctor.
  • Do not use Linevox to treat any other medical complaints unless your doctor tells you to.
  • Do not start taking any other medicines without first telling your doctor or pharmacist.
Driving or using machines
  • Be careful driving or operating machinery until you know how Linevox affects you.
  • This medicine may cause dizziness and visual impairment in some people. Children should be careful performing activities requiring attention such as riding bicycles or climbing.
Drinking alcohol
  • Avoid drinking alcohol, especially draught beers and wine.
Looking after your medicine
  • Store Linevox tablets in original carton at below 30°C until ready for use.

For more information, see Section 5. What should I know while using Linevox? in the full CMI.

6. Are there any side effects?

Side effects of this medicine may include headache; sore white mouth or tongue; vaginal itching or discharge; abdominal pain or bloating; nausea; vomiting; metallic taste; change in colour of tongue or teeth; difficulty concentrating; memory or visual impairment; confusion; tiredness; dizziness; rash, itching or hives or blisters on skin; numbness or weakness of arms or legs; shortness of breath; sweating; seizure; fainting; coma; swelling of face or lips; bleeding in lips, eyes, mouth, nose and genitals; painful red/purple spots with/without blisters and peeling of skin, may be accompanied by fevers, chills, aching muscles, dehydration, dark urine, reduce urine, no urine, joint pain, enlarged lymph nodes and generally feeling unwell.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

LINEVOX

Active ingredient(s): Linezolid

Consumer Medicine Information (CMI)

This leaflet provides important information about using Linevox. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Linevox.

Where to find information in this leaflet:

1. Why am I using Linevox?
2. What should I know before I use Linevox?
3. What if I am taking other medicines?
4. How do I use Linevox?
5. What should I know while using Linevox?
6. Are there any side effects?
7. Product details

1. Why am I using Linevox?

Linevox contains the active ingredient Linezolid. It 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 may have prescribed it for another reason. Ask your doctor if you have any questions about why Linevox has been prescribed for you or your child.

2. What should I know before I use Linevox?

Warnings

Do not use Linevox if you or your child have the following medical conditions:

  • allergic to linezolid, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or troubled breathing.

  • uncontrolled high blood pressure
  • pheochromocytoma (a type of tumour of the adrenal gland)
  • thyrotoxicosis (an overactive thyroid gland)
  • flushing or other symptoms caused by a carcinoid tumour

Do not use Linevox if you or your child are taking any of the following medicines:

  • 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 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)
  • buspirone, a medicine to treat anxiety
  • some medicines to treat migraine (e.g. naratriptan, sumatriptan, zolmitriptan)
  • pethidine, a medicine to treat pain
  • 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).

Do not use Linevox if:

  • the packaging is torn or shows signs of tampering
  • the expiry date printed on the pack has passed.

Tell your doctor if you or your child have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you or your child:

  • have diarrhoea
  • have phenylketonuria
  • are anaemic or have had any abnormal blood test results (e.g. low haemoglobin or platelets)
  • are diabetic
  • have kidney or liver problems.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risks and benefits involved.

Linevox is not addictive.

3. What if I am taking other medicines?

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

Some medicines and Linevox may interfere with each other. These include:

  • any medicine that inhibits monoamine oxidase (e.g. moclobemide, phenelzine or tranylcypromine to treat depression or selegiline to treat Parkinson's disease)
  • 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)
  • buspirone, a medicine to treat anxiety
  • some medicines to treat migraine (e.g. naratriptan, sumatriptan, zolmitriptan)
  • any medicine that is an opioid, a medicine to treat pain
  • 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)
  • 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).

These medicines may be affected by Linevox or may affect how well it works. You or your child may need different amounts of medicines or may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

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.

Linevox may react with a substance which is naturally present in these foods.

4. How do I use LINEVOX?

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).

Continue taking Linevox until you or your child finish the tablets unless your doctor recommends otherwise.

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

Do not stop giving Linevox 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.

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

How Linevox is given

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

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.

When to take Linevox

Linevox can be taken before, during or after meals.

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

If you forget to take Linevox

Linevox should be taken regularly at the same time each day If you miss your dose at the usual time, ask your doctor or pharmacist for advice.

If you use too much Linevox

If you think that you or your child have used too much Linevox, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose are vomiting, tremors (shaking), unsteadiness or lack of coordination.

5. What should I know while using Linevox?

Things you should do

If you or your child are about to be started on any new medicine, remind your doctor and pharmacist that you or your child are taking Linevox.

Tell any other doctors, dentists and pharmacists who are treating you or your child that you are taking Linevox.

If you or your child are going to have surgery, tell the surgeon or anaesthetist that you or your child are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while you are being treated with Linevox, tell your doctor immediately.

Keep all of your doctor's appointments so that your or your child's progress can be checked.

Your doctor may do some blood tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

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 Linevox 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 Linevox. Do this even if it occurs several weeks after Linevox 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 Linevox 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 Linevox allows fungi to grow which causes the symptoms described above. Linevox does not work against fungi.

Things you should not do

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

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen.

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.

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 Linevox 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Linevox affects you.

This medicine may cause dizziness and visual impairment in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Children should be careful performing activities requiring attention such as riding bicycles or climbing.

Drinking alcohol

Avoid drinking alcohol, especially draught beers and wine.

Looking after your medicine

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

Keep Linevox tablets in a cool dry place where the temperature stays below 30°C.

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

Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep Linevox 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.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

6. Are there any side effects?

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

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Do not be alarmed by the following lists of side effects.

You or your child may not experience any of them.

Less serious side effects

Less Serious Side effectsWhat to do
  • 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.
  • difficulty concentrating, memory impairment, confusion, weakness and unsteadiness, which may lead to falls (these symptoms may indicate low sodium levels in the blood).
Speak to your doctor if you have any of these less side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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.

  • seizure
  • hallucination
  • fainting
  • coma
  • 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.
  • painful red/purple spots with/ without blisters and peeling of skin. This may be accompanied by fevers and chills, aching muscles, joint pain, enlarged lymph nodes and generally feeling unwell.
  • muscle aching or swelling
  • lack of consciousness
  • dehydration
  • dark red or brown urine, or reduced or no urine
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

These are serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

After finishing Linevox 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 Linevox:

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

Linevox 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 doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Linevox 600 mg tablet contains

Active ingredient
(Main ingredient)		linezolid
Other ingredients
(Inactive ingredients)
  • microcrystalline cellulose
  • sodium starch glycollate type A
  • magnesium stearate
  • poloxamer
  • povidone
  • colloidal anhydrous silica
  • lactose monohydrate
  • talc
  • OPADRY II Complete Film Coating System YS-1-18202-A White
  • Videojet InkSource 16-9000 Ink (blue printing ink)

This medicine contains Lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What Linevox looks like

Linevox tablets are white oval biconvex tablets, printed with '600' on one side. The tablets are available in blister packs of 10 tablets.

AUST R 237304 (blister pack)

Who distributes Linevox?

Arrotex Pharmaceuticals Pty Ltd
15 - 17 Chapel Street
Cremorne
Victoria 3121
www.arrotex.com.au

This leaflet was prepared in December 2023

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Linevox

Active ingredient

Linezolid

Schedule

S4

 

1 Name of Medicine

Linezolid.

2 Qualitative and Quantitative Composition

Linevox tablets contain 600 mg of linezolid.

Physical and chemical characteristics.

Linezolid is a synthetic antibacterial agent of the oxazolidinone class with a molecular weight of 337.35. Linezolid is biologically active and is metabolised to form inactive derivatives. The aqueous solubility of linezolid is approximately 3 mg/mL, independent of pH between pH 3 to 9.

Excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Linevox film-coated tablets are white oval biconvex tablets, printed with '600' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Linezolid 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.
Linezolid is active against Gram-positive bacteria only. Linezolid 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

Patients who commence treatment on the parenteral# formulation may be switched to either tablet or suspension# oral presentations when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.
The film coated tablets may be taken with or without food.
The maximum recommended duration of treatment is 28 days.
# Linezolid injection and oral suspension are unavailable in Linevox brand however are available in other brands. Where correct dosing requires injection or oral suspension formulations in paediatric or adult patients, the injection or oral suspension formulations from other suppliers should be used.

Adults and children 12 years or older.

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

Dosage adjustments in special populations.

No dose adjustment is required in the elderly, in patients with impaired hepatic function or impaired renal function. However, linezolid 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 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 re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 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 linezolid should be initiated in a hospital environment following guidance from appropriate specialists.
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 pre-treatment levels when linezolid was discontinued.
Thrombocytopenia may occur more often in patients with severe renal insufficiency, whether or not on dialysis, and in patients with moderate to severe hepatic impairment. Complete blood counts should be monitored weekly in patients who receive linezolid for longer than two weeks, particularly those with pre-existing myelosuppression, who have severe renal insufficiency or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression or may decrease haemoglobin levels or platelet count or function, 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 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 linezolid 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 linezolid 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 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 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.
Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids have been reported (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Rhabdomyolysis has been reported with the use of linezolid. If signs or symptoms of rhabdomyolysis are observed, linezolid should be discontinued and appropriate therapy initiated.
Hyponatraemia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in some patients treated with linezolid. It is recommended that serum sodium levels be monitored regularly in the elderly, in patients taking diuretics, and in other patients at risk of hyponatraemia.
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.
The use of antibiotics may occasionally result in an overgrowth of non-susceptible 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 for 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, randomized 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 pathogen were identified at baseline. Patients randomized 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 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.

Use in 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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Elderly.

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 inter-subject variation in this age group compared with adults (see Section 5.2 Pharmacokinetic Properties, Special populations, Paediatric). Results of clinical studies showed similar efficacy in adult and adolescent patients. Given the wider inter-subject variation in adolescents, the slight possibility that high clearance may result in decreased efficacy in some adolescent patients should be considered. The dosage for paediatric 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 6 (83%) paediatric patients with infections due to Gram-positive pathogens with MICs of 4 microgram/mL treated with linezolid had clinical cures. However, paediatric patients with a sub-optimal 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 5.2 Pharmacokinetic Properties, Special populations, Paediatric; Section 4.2 Dose and Method of Administration).

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 linezolid. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). Limited clinical studies have shown that co-administration of linezolid 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 co-administered with linezolid (see Section 4.3 Contraindications).
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 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).
Linezolid has the potential for interaction with serotonergic agents. Limited clinical studies have shown that co-administration of linezolid 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 co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), and opioids, have been reported (see Section 4.3 Contraindications). Patients who are treated with linezolid 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 (linezolid 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 twice daily 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 AUCs) 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 non-viable. 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 linezolid in pregnant women. Studies in animals have shown reproductive effects (see below). The potential risk for humans is unknown.
Linezolid 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.
Embryo fetal 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 body weights 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 body weight gain).
Linezolid was also not teratogenic in rabbits, when administered twice daily 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 body weight 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 (as described in Special Warnings and Precautions for Use and 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)

Clinical trials.

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 linezolid doses for up to 28 days. In these studies, the majority of adverse reactions to linezolid 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 linezolid 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 linezolid 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 linezolid 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 linezolid 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 surveillance.

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, anaphylaxis and hypersensitivity vasculitis have been reported. Very rare reports of bullous skin disorders including severe cutaneous adverse reactions such as those described 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 linezolid (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.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis has been reported with the use of linezolid (see Section 4.4 Special Warnings and Precautions for Use).

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific antidote is known.
No cases of overdose have been reported. However, the following may prove to be useful:
Symptomatic and supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis. 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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

General properties. Linezolid is a synthetic, antibacterial agent belonging to a new 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 non-susceptible 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 non-susceptible to linezolid. In clinical trials, resistance to linezolid developed in 6 patients infected with E. faecium (4 patients received 200 mg twice daily, lower than the recommended dose, and 2 patients received 600 mg twice daily). 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 non-susceptible enterococci are identified, strict infection control measures and adherence to antibiotic guidelines should be maintained.

Clinical trials.

Adult. There are no data from comparator controlled clinical trials on the use of linezolid 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, multi-centre, double-blind clinical trial. Patients were treated for 7 to 21 days. One group (No. enrolled = 205) received linezolid injection# 600 mg twice daily (bid), and another group (No. enrolled = 197) received vancomycin 1 g bid intravenously (IV). Both groups received concomitant aztreonam (1 to 2 g every 8 hours IV). Linezolid 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 linezolid 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, multi-centre 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 linezolid injection# (600 mg bid) followed by linezolid 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 linezolid tablets 600 mg bid (No. enrolled = 278) and another group received cefpodoxime proxetil tablets 200 mg bid (No. enrolled = 270).
In these trials, linezolid demonstrated efficacy equivalent to ceftriaxone or cefpodoxime proxetil by all outcome measurements. The overall clinical cure rates in the ITT population in linezolid 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, multi-centre, 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 linezolid injection# (600 mg bid) followed by linezolid 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. Linezolid 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 linezolid 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, multi-centre, open-label trial. One group of patients (No. enrolled = 243) received linezolid injection# 600 mg bid followed by linezolid 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. Linezolid 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 was 57% in the linezolid 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, multi-centre, 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 linezolid 600 mg bid IV or orally in an open-label, non-comparative, 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 linezolid in paediatric patients for the treatment of hospital acquired pneumonia, complicated skin and skin structure infections, catheter-related bacteremia, bacteremia 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 linezolid IV Injection# 10 mg/kg every 8 hours followed by linezolid 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 linezolid 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) oral dosing are given in Table 14.
As can be seen from Table 14, average Cmin values achieved in plasma using the 600 mg twice daily 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%. Steady-state conditions are achieved by the second or third day of dosing.
Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ values is similar under both conditions.

Distribution.

Linezolid is readily distributed to well perfused tissues. Its volume of distribution at steady-state averages at 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 non-inflamed 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 non-enzymatic 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.
Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.

Special populations.

Paediatric.

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 adult 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 pre-term neonates less than one week of age, clearance is most rapid in the youngest age groups ranging from > 1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of 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 inter-subject 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 pre-term neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full term neonates and older infants. Therefore, these pre-term neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of a 10 mg/kg every 8 hours regimen in neonates with a sub-optimal 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).

Elderly (> 65 years).

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

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.

Renal insufficiency.

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), linezolid 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 insufficiency.

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 non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.

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

Linevox tablets contain, in the core, microcrystalline cellulose, sodium starch glycollate type A, magnesium stearate, poloxamer, povidone, colloidal anhydrous silica, lactose monohydrate, purified talc and, in the film coating, Opadry Aqueous Film Coating YS-1-18202-A White (proprietary ingredient number 11935) and Videojet InkSource 16-9000 Ink (blue printing ink) (proprietary ingredient number 4632).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Linevox 600 mg film-coated tablets are available in PVC/PE/PVDC/Al or Al/Al blister of 10s.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide.
The empirical formula of linezolid is C16H20FN3O4 and its chemical structure is represented below:

CAS number.

CAS-165800-03-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription only medicine).

Summary Table of Changes