Linezolid 600mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Linezolid
Available from:
Mylan
ATC code:
J01XX08
INN (International Name):
Linezolid
Dosage:
600mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05010700; GTIN: 5016695007052
Authorization number:
PL 04569/1640

Read the complete document

Package leaflet: Information for the patient

Linezolid 600 mg Film-coated Tablets

linezolid

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What Linezolid is and what it is used for

What you need to know before you take Linezolid

How to take Linezolid

Possible side effects

How to store Linezolid

Contents of the pack and other information

1.

What Linezolid is and what it is used for

Linezolid is a medicine containing the active substance linezolid which is an antibiotic of the oxazolidinones

group. This medicine works by stopping the growth of certain bacteria (germs) that cause infections. It is used to

treat pneumonia and some infections in the skin or under the skin. Your doctor will have decided if Linezolid is

suitable to treat your infection.

2.

What you need to know before you take Linezolid

Do not take Linezolid

If you are allergic to linezolid or any of the other ingredients of this medicine (listed in section 6).

If you are taking or have taken within the last 2 weeks any medicines known as monoamine oxidase inhibitors

(MAOIs, for example phenelzine, isocarboxazid, selegiline, moclobemide). These may be used to treat

depression or Parkinson’s disease.

If you are breast-feeding. This is because it passes into breast milk and could affect the baby.

Linezolid may not be suitable for you if you answer yes

to any of the following questions. In this case tell your

doctor as he/she will need to check your general health and your blood pressure before and during your treatment,

or may decide that another treatment is better for you.

Ask your doctor if you are not sure whether these categories apply to you.

Do you have high blood pressure not controlled by medicines?

Have you been diagnosed with an overactive thyroid?

Do you have a tumour of the adrenal glands (phaeochromocytoma) or carcinoid syndrome (caused by tumours of

the hormone system with symptoms of diarrhoea, flushing of the skin, wheezing)?

Do you suffer from manic depression, schizoaffective disorder, mental confusion or other mental health

problems?

Are you taking or are likely to take any of the following medicines?

decongestant, cold or flu remedies containing pseudoephedrine or phenylpropanolamine

medicines used to treat asthma such as salbutamol, terbutaline or fenoterol

antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors) for

example amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine,

imipramine, lofepramine, paroxetine or sertraline

medicines used to treat migraine such as sumatriptan and zolmitriptan

medicines used to treat sudden, severe allergic reactions such as adrenaline (epinephrine)

medicines which increase your blood pressure, such as noradrenaline (norepinephrine),

dopamine and dobutamine

pethidine, a medicine used to treat moderate to severe pain

buspirone, a medicine used to treat anxiety disorders.

Warnings and precautions

Talk to your doctor or pharmacist before taking Linezolid if you

bruise and bleed easily

are anaemic (have low red blood cells)

are prone to getting infections

have a history of seizures

have liver problems or serious kidney problems particularly if you have dialysis

have diarrhoea

have recently been treated or are being treated for tuberculosis.

Tell your doctor immediately if during treatment you notice any of the following:

unexplained bruising, bleeding more easily than normal, pale skin with shortness of breath or more frequent

infections.

problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or if your

field of vision becomes restricted.

tingling or pricking in your arms or legs, loss of balance or coordination, feeling faint when standing up, a cut or

ulcer on your foot that is not getting better or changes to your normal bowel and bladder function.

you may develop diarrhoea while taking or after taking antibiotics, including linezolid. If this becomes severe or

persistent or you notice that your stools contains blood or mucus, you should stop taking linezolid immediately

and consult your doctor. In this situation, you should not take medicines that stop or slow bowel movement.

repeated nausea (feeling sick) or vomiting (being sick), stomach pain or rapid breathing.

Children and adolescents

Use of linezolid is not recommended for children and adolescents (under 18 years old).

Other medicines and Linezolid

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines,

including medicines obtained without prescription.

There is a risk that linezolid may sometimes interact with certain other medicines to cause side effects such as

changes in blood pressure, temperature or heart rate.

Tell your doctor if you are taking or have taken within the last 2 weeks the following medicines as Linezolid

must not

be taken (see also Section 2 above ‘Do not use Linezolid’).

monoamine oxidase inhibitors (MAOIs, for example phenelzine, isocarboxazid, selegiline, moclobemide).

These may be used to treat depression or Parkinson’s disease.

Also tell your doctor if you are taking or likely to take the following medicines. Your doctor may still decide to

give you Linezolid, but will need to check your general health and your blood pressure before and during your

treatment. In other cases, your doctor may decide that another treatment is better for you.

Decongestant cold or flu remedies containing pseudoephedrine or phenylpropanolamine.

Some medicines used to treat asthma such as salbutamol, terbutaline, fenoterol.

Certain antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many of

these, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine,

lofepramine, paroxetine, sertraline.

Medicines used to treat migraine such as sumatriptan and zolmitriptan.

Medicines used to treat sudden, severe allergic reactions such as adrenaline (epinephrine).

Medicines which increase your blood pressure, such as noradrenaline (norepinephrine), dopamine and

dobutamine.

Pethidine, a medicine used to treat moderate to severe pain.

Buspirone, a medicine used to treat anxiety disorders.

Warfarin, a medicine that stop blood clotting.

Dextromethorphan, a medicine used to relieve dry coughs.

Rifampicin, an antibiotic medicine used to treat some infections.

Medicines that affect the levels of blood cells such as antiretroviral or chemotherapy medicines.

Linezolid with food, drink and alcohol

Avoid eating large amounts of mature cheese, yeast extracts, or soya bean extracts e.g. soy sauce and drinking

alcohol, especially draught beers and wine. This is because this medicine may react with a substance called

tyramine which is naturally present in some foods to cause an increase in your blood pressure.

If you develop a throbbing headache have blurred vision, difficulty thinking, chest pain, a fit, feel sick (nausea) or

are sick (vomiting) after eating or drinking, tell your doctor or pharmacist immediately.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding think you may be pregnant or are planning to have a baby, ask your doctor or

pharmacist for advice before taking this medicine.

Pregnancy

The effect of linezolid in pregnant women is not known. Therefore, it should not be taken in pregnancy unless

advised by your doctor.

Breast-feeding

You must not breast-feed when taking linezolid because it passes into breast milk and could affect the baby.

Driving and using machines

Linezolid may make you feel dizzy or experience problems with your vision. If this happens, do not drive or operate

any machinery. Remember that if you are unwell your ability to drive or operate machinery may be affected.

3. How to take Linezolid

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if

you are not sure.

The recommended dose is one tablet (600 mg linezolid) twice daily (every twelve hours). Swallow the tablet whole

with some water. You can take Linezolid either before, during or after a meal.

If you are on kidney dialysis, you should take linezolid after dialysis.

A course of treatment usually lasts 10 to 14 days but can last up to 28 days. The safety and effectiveness of this

medicine have not been established for treatment periods longer than 28 days. Your doctor will decide how long you

should be treated.

While you are taking linezolid, your doctor should perform regular blood tests to monitor your blood count.

Your doctor should monitor your eyesight if you take linezolid for more than 28 days.

Use in children and adolescents

Linezolid is not normally used to treat children and adolescents (under 18 years old).

If you take more Linezolid than you should

Tell your doctor or pharmacist immediately.

If you forget to take Linezolid

Take the forgotten tablet as soon as you remember. Take the next tablet 12 hours after this and continue taking your

tablets every 12 hours. Do not take a double dose to make up for a forgotten dose.

If you stop taking Linezolid

Unless your doctor instructs you to stop treatment, it is important to continue taking linezolid.

If you stop and your original symptoms come back tell your doctor or pharmacist immediately.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or pharmacist immediately

if you notice any of these side effects during your treatment with

linezolid, or if serious, go to your nearest hospital emergency department:

Uncommon

(may affect up to 1 in 100 people):

leukopenia, neutropenia: decrease in the number of white blood cells which makes you prone to getting

infections.

fits or seizures.

transient ischaemic attacks: temporary disturbance of blood flow to the brain causing short term symptoms such

as loss of vision, leg and arm weakness, slurring of speech and loss of consciousness.

severe stomach pain which radiates to your back. These may be signs of problems with your pancreas.

passing little or no urine, pain, discomfort or difficulty when passing urine, cloudy urine or lower back pain.

These may indicate a serious problem with your kidneys.

problems with your vision such as blurred vision, changes in colour vision, loss of vision, pain on moving the

eye, difficulty in seeing detail or if your field of vision becomes restricted.

Rare

(may affect up to 1 in 1,000 people):

severe or persistent diarrhoea containing blood and/or mucus (antibiotic associated colitis including

pseudomembranous colitis), which in rare circumstances may develop into complications that are life-

threatening.

pale skin with shortness of breath, have unexplained bruising or bleed for longer than normal together with signs

of low levels of white blood cells (see above). These may be signs you have low levels of all blood cells.

Not known

(frequency cannot be estimated from the available data):

rash, itching, or swelling, particularly around the face, lips, mouth, tongue and neck with difficulty breathing or

swallowing. These may be signs of an allergic reaction and it may be necessary for you to stop taking linezolid.

loss of sensitivity in your arms or legs which you may notice as tingling or pricking in your arms or legs, loss of

balance or coordination, feeling faint when standing up, a cut or ulcer on your foot that is not getting better,

changes to your normal bowel and bladder function. These may be signs of nerve damage.

repeated nausea (feeling sick) or vomiting (being sick), stomach pain or rapid breathing (symptoms of lactic

acidosis).

fast heart rate, confusion, abnormal sweating, either hearing, seeing or feeling things that are not there

(hallucinations), twitching, shaking, fits, chills and shivering. These may be signs you have too much of a

chemical in your body called serotonin.

serious skin reactions such as a widespread rash with blisters, bleeding from the nose, mouth, eyes or genitals

(Stevens-Johnson syndrome) or peeling of large areas of skin (toxic epidermal necrolysis).

Other possible side effects include:

Common

(may affect up to 1 in 10 people):

Fungal infections especially vaginal or oral ‘thrush’

Difficulty in sleeping

Headache

Metallic taste in the mouth

Dizziness

Increased blood pressure

Diarrhoea, nausea (feeling sick) or vomiting (being sick)

Indigestion, stomach pain, constipation

Changes in some blood test results including those measuring your kidney or liver function or blood sugar

levels

Changes in numbers of certain cells in the blood, seen in a blood test

Itchy skin, skin rash

Decrease in the amount of red blood cells (anaemia)

Fever

Pain.

Uncommon

(may affect up to 1 in 100 people):

Inflammation of the vagina or genital area in women or other problems with the genital area

Unexplained bruising or bleeding for longer than normal. These may be signs of low levels of platelets in

your blood

Low levels of sodium in the blood which can be seen in a blood test

Sensations such as tingling or feeling numb

Ringing in the ears (tinnitus)

Changes in the heart rate (e.g. increase in rate)

Redness, swelling and pain along a vein which may due to a clot

Dry or sore, red or inflamed mouth with mouth ulcers

Pain, nausea (feeling sick), vomiting (being sick) which may contain blood, blood in stools. These may be

signs of inflammation of the stomach lining

Bloated stomach

Swollen, sore or discoloured tongue

Other problems with your tongue

Loose stools

Nettle rash, red sore skin and flaking (dermatitis)

Producing large amounts of urine with a need to urinate more often

Chills

Feeling tired or thirsty

Increased sweating

Changes in proteins, salts or enzymes in the blood which measure kidney or liver function.

Rare

(may affect up to 1 in 1,000 people):

Changes to the colour of your teeth which can be removed with professional dental cleaning.

Not known

(frequency cannot be estimated from the available data):

Hair loss (alopecia).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in

this leaflet. You can also report side effects directly via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help

provide more information on the safety of this medicine.

5. How to store Linezolid

Keep this medicine out of the sight and reach of children.

This medicine does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the carton and blister pack after EXP. The expiry

date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Linezolid contains

The active substance is linezolid. Each film-coated tablet contains 600 mg linezolid.

The other ingredients are microcrystalline cellulose (E460), crospovidone hydroxypropylcellulose (E463),

colloidal anhydrous silica and magnesium stearate (E572). The film-coating contains hypromellose

(E464), titanium dioxide (E171), macrogol 400.

What Linezolid looks like and contents of the pack

Linezolid

are white to off-white, oblong, curved on both sides film-coated tablets marked with “L9II 600”

on one side.

Each carton contains either 1, 10, 20, 30, 50, 60 or 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire, EN6 1TL. United Kingdom.

Manufacturer(s)

Synthon BV

Microweg 22

6545 CM Nijmegen

The Netherlands

Synthon Hispania SL

C/Castelló n°1, Pol. Las Salinas

08830 Sant Boi de Lloberegat (Barcelona)

Spain

This leaflet was last revised in

11/2017.

Read the complete document

Object 1

Linezolid 600 mg Film-coated Tablets

Summary of Product Characteristics Updated 31-May-2018 | Generics UK T/A Mylan

1. Name of the medicinal product

Linezolid 600 mg Film-coated Tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 600 mg linezolid.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

White to off-white, oblong (approximately 18 mm x 6 mm), biconvex film coated tablets debossed with

“L9II 600” on one side.

4. Clinical particulars

4.1 Therapeutic indications

Nosocomial pneumonia.

Community acquired pneumonia.

Linezolid is indicated in adults for the treatment of community acquired pneumonia and nosocomial

pneumonia when known or suspected to be caused by susceptible Gram positive bacteria. In determining

whether linezolid is an appropriate treatment, the results of microbiological tests or information on the

prevalence of resistance to antibacterial agents among Gram positive bacteria should be taken into

consideration (see section 5.1 for the appropriate organisms).

Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy against

Gram negative organisms must be initiated concomitantly if a Gram negative pathogen is documented or

suspected.

Complicated skin and soft tissue infections (see section 4.4).

Linezolid is indicated in adults for the treatment of complicated skin and soft tissue infections only when

microbiological testing has established that the infection is known to be caused by susceptible Gram

positive bacteria.

Linezolid is not active against infections caused by Gram negative pathogens. Linezolid should only be

used in patients with complicated skin and soft tissue infections with known or possible co-infection with

Gram negative organisms if there are no alternative treatment options available (see section 4.4). In these

circumstances treatment against Gram negative organisms must be initiated concomitantly.

Linezolid should only be initiated in a hospital environment and after consultation with a relevant

specialist such as a microbiologist or infectious diseases specialist.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

Linezolid solution for infusion, film-coated tablets or oral suspension may be used as initial therapy.

Patients who commence treatment on the parenteral formulation may be switched to either oral

presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid

has an oral bioavailability of approximately 100%.

Recommended dosage and duration of treatment for adults:

The duration of treatment is dependent on the pathogen, the site of infection and its severity, and on the

patient's clinical response.

The following recommendations for duration of therapy reflect those used in the clinical trials. Shorter

treatment regimens may be suitable for some types of infection but have not been evaluated in clinical

trials.

The maximum treatment duration is 28 days. The safety and effectiveness of linezolid when administered

for periods longer than 28 days have not been established (see section 4.4).

No increase in the recommended dosage or duration of treatment is required for infections associated with

concurrent bacteraemia.

The dose recommendation for the solution for infusion and the tablets/granules for oral suspension are

identical and are as follows:

Infections

Dosage

Duration of treatment

Nosocomial pneumonia

600 mg twice daily

10-14 Consecutive days

Community acquired pneumonia

Complicated skin and soft tissue

infections

600 mg twice daily

Paediatric population:

The safety and efficacy of linezolid in children aged (< 18 years old) has not been established. Currently

available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be

made.

Elderly:

No dose adjustment is required.

Renal impairment:

No dose adjustment is required (see sections 4.4 and 5.2).

Severe renal impairment (i.e. CL

CR

< 30 ml/min):

No dose adjustment is required. Due to the unknown clinical significance of higher exposure (up to 10

fold) to the two primary metabolites of linezolid in patients with severe renal insufficiency, linezolid

should be used with special caution in these patients and only when the anticipated benefit is considered

to outweigh the theoretical risk.

As approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, linezolid should

be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid are

removed to some extent by haemodialysis, but the concentrations of these metabolites are still very

considerably higher following dialysis than those observed in patients with normal renal function or mild

to moderate renal insufficiency.

Therefore, linezolid should be used with special caution in patients with severe renal insufficiency who

are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical

risk.

To date, there is no experience of linezolid administration to patients undergoing continuous ambulatory

peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis).

Hepatic impairment:

No dose adjustment is required. However, there are limited clinical data and it is recommended that

linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the

theoretical risk (see sections 4.4 and 5.2).

Method of administration:

For oral use.

The film-coated tablets may be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases

A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such

medicinal product.

Unless there are facilities available for close observation and monitoring of blood pressure, linezolid

should not be administered to patients with the following underlying clinical conditions or on the

following types of concomitant medications:

- Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar

depression, schizoaffective disorder, acute confusional states.

- Patients taking any of the following medications: serotonin re-uptake inhibitors (see section 4.4),

tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), directly and indirectly acting

sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and

phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g.

dopamine, dobutamine), pethidine or buspirone.

Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breast-

feeding should be discontinued prior to and throughout administration (see section 4.6).

4.4 Special warnings and precautions for use

Myelosuppression

Myelosuppression (including anaemia, leukopenia, pancytopenia and thrombocytopenia) has been

reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was

discontinued, the affected haematologic parameters have risen toward pretreatment levels. The risk of

these effects appears to be related to the duration of treatment. Elderly patients treated with linezolid may

be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur

more commonly in patients with severe renal insufficiency, whether or not on dialysis. Therefore, close

monitoring of blood counts is recommended in patients who: have pre-existing anaemia,

granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease

haemoglobin levels, depress blood counts or adversely affect platelet count or function; have severe renal

insufficiency; receive more than 10-14 days of therapy. Linezolid should be administered to such patients

only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible.

If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is

considered absolutely necessary to continue therapy, in which case intensive monitoring of blood counts

and appropriate management strategies should be implemented.

In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and

total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid

regardless of baseline blood count.

In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving

linezolid for more than the maximum recommended duration of 28 days. These patients more often

required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post

marketing, with more cases occurring in patients who received linezolid therapy for more than 28 days.

Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most

patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered

following discontinuation of linezolid with or without treatment for their anaemia.

Mortality imbalance in a clinical trial in patients with catheter-related Gram positive bloodstream

infections

Excess mortality was seen in patients treated with linezolid, relative to

vancomycin/dicloxacillin/oxacillin, in an open-label study in seriously ill patients with intravascular

catheter-related infections [78/363 (21.5%) vs 58/363 (16.0%)]. The main factor influencing the mortality

rate was the Gram positive infection status at baseline. Mortality rates were similar in patients with

infections caused purely by Gram positive organisms (odds ratio 0.96; 95% confidence interval: 0.58-

1.59) but were significantly higher (p=0.0162) in the linezolid arm in patients with any other pathogen or

no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38-4.46). The greatest imbalance

occurred during treatment and within 7 days following discontinuation of study drug. More patients in the

linezolid arm acquired Gram negative pathogens during the study and died from infection caused by

Gram negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue

infections linezolid should only be used in patients with known or possible co-infection with Gram

negative organisms if there are no alternative treatment options available (see section 4.1). In these

circumstances treatment against Gram negative organisms must be initiated concomitantly.

Antibiotic-associated diarrhoea and colitis

Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and

Clostridium difficile-associated diarrhoea, has been reported in association with the use of nearly all

antibiotics including linezolid and may range in severity from mild diarrhoea to fatal colitis. Therefore, it

is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of

linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed,

ongoing treatment with antibacterial agents, including linezolid, should be discontinued and adequate

therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in

this situation.

Lactic acidosis

Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of

metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or

hyperventilation while receiving linezolid should receive immediate medical attention. If lactic acidosis

occurs, the benefits of continued use of linezolid should be weighed against the potential risks.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and

neuropathy (optic and peripheral), may occur as a result of this inhibition; these events are more common

when the drug is used longer than 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and

serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs)

have been reported. Co-administration of linezolid and serotonergic agents is therefore contraindicated

(see section 4.3) except where administration of linezolid and concomitant serotonergic agents is

essential. In those cases patients should be closely observed for signs and symptoms of serotonin

syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or

symptoms occur physicians should consider discontinuing either one or both agents; if the concomitant

serotonergic agent is withdrawn, discontinuation symptoms can occur.

Peripheral and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis 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.

All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity,

changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is

recommended with referral to an ophthalmologist as necessary. If any patients are taking linezolid for

longer than the recommended 28 days, their visual function should be regularly monitored.

If peripheral or optic neuropathy occurs, the continued use of linezolid should be weighed against the

potential risks.

There may be an increased risk of neuropathies when linezolid is used in patients currently taking or who

have recently taken antimycobacterial medications for the treatment of tuberculosis.

Convulsions

Convulsions have been reported to occur in patients when treated with linezolid.

In most of these cases, a history of seizures or risk factors for seizures was reported. Patients should be

advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI); however, at the doses

used for antibacterial therapy, it does not exert an anti-depressive effect. There are very limited data from

drug interaction studies and on the safety of linezolid when administered to patients with underlying

conditions and/or on concomitant medications which might put them at risk from MAO inhibition.

Therefore, linezolid is not recommended for use in these circumstances unless close observation and

monitoring of the recipient is possible (see sections 4.3 and 4.5).

Use with tyramine-rich foods

Patients should be advised against consuming large amounts of tyramine rich foods (see section 4.5).

Superinfection

The effects of linezolid therapy on normal flora have not been evaluated in clinical trials.

The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For

example, approximately 3% of patients receiving the recommended linezolid doses experienced drug-

related candidiasis during clinical trials. Should superinfection occur during therapy, appropriate

measures should be taken.

Special populations

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 (see sections 4.2 and 5.2).

It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when

the perceived benefit outweighs the theoretical risk (see sections 4.2 and 5.2).

Impairment of fertility

Linezolid reversibly decreased fertility and induced abnormal sperm morphology in adult male rats at

exposure levels approximately equal to those expected in humans; possible effects of linezolid on the

human male reproductive system are not known (see section 5.3).

Clinical trials

The safety and effectiveness of linezolid when administered for periods longer than 28 days have not

been established.

Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic

lesions, severe burns or gangrene. Therefore, experience in the use of linezolid in the treatment of these

conditions is limited.

4.5 Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are very limited

data from drug interaction studies and on the safety of linezolid when administered to patients on

concomitant medications that might put them at risk from MAO inhibition. Therefore, linezolid is not

recommended for use in these circumstances unless close observation and monitoring of the recipient is

possible (see sections 4.3 and 4.4).

Potential interactions producing elevation of blood pressure

In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by

pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of linezolid with either

pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the

order of 30-40 mmHg, compared with 11-15 mmHg increases with linezolid alone, 14-18 mmHg with

either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in

hypertensive subjects have not been conducted. It is recommended that doses of drugs with a

vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired

response when co-administered with linezolid.

Potential serotonergic interactions

The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects

were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No

serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis,

hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

Post marketing experience: there has been one report of a patient experiencing serotonin syndrome-like

effects while taking linezolid and dextromethorphan which resolved on discontinuation of both

medications.

During clinical use of linezolid with serotonergic agents, including antidepressants such as selective

serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been reported. Therefore, while

co-administration is contraindicated (see section 4.3), management of patients for whom treatment with

linezolid and serotonergic agents is essential, is described in section 4.4.

Use with tyramine-rich foods

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).

Drugs metabolised by cytochrome P450

Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not

inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-induced drug

interactions are expected with linezolid.

Rifampicin

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 C

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.

Warfarin

When warfarin was added to linezolid therapy at steady-state, there was a 10% reduction in mean

maximum INR on co-administration with a 5% reduction in AUC INR. There are insufficient data from

patients who have received warfarin and linezolid to assess the clinical significance, if any, of these

findings.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of linezolid in pregnant women. Studies in animals have shown

reproductive toxicity (see section 5.3). A potential risk for humans exists.

Linezolid should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit

outweighs the theoretical risk.

Breast-feeding

Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breast-

feeding should be discontinued prior to and throughout administration.

Fertility

In animal studies, linezolid caused a reduction in fertility (see section 5.3).

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 section 4.4 and 4.8) whilst receiving linezolid and should be advised not to drive or operate

machinery if any of these symptoms occurs.

4.8 Undesirable effects

The table below provides a listing of adverse drug reactions with frequency based on all-causality data

from clinical studies that enrolled more than 2,000 adult patients who received the recommended

linezolid doses for up to 28 days.

Those most commonly reported were diarrhoea (8.4%), headache (6.5%), nausea (6.3%) and vomiting

(4.0%). The most commonly reported drug-related adverse events which led to discontinuation of

treatment were headache, diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment

because they experienced a drug-related adverse event.

Additional adverse reactions reported from post-marketing experience are included in the table with

frequency category 'Not known', since the actual frequency cannot be estimated from the available data.

The following undesirable effects have been observed and reported during treatment with linezolid with

the following frequencies: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to

<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from

the available data).

System Organ

Class

Common (≥1/100

to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to

<1/1,000)

Not known (frequency

cannot be estimated

from the available data)

Infections and

infestations

Candidiasis, oral

candidiasis, vaginal

candidiasis, fungal

infections

Vaginitis

Antibiotic-

associated colitis,

including

pseudomembranous

colitis*

Blood and the

lymphatic

system disorders

Anaemia*

Leucopenia*,

neutropenia,

thrombocytopenia*,

eosinophilia

Pancytopenia*

Myelosuppression*,

sideroblastic anaemia*

Immune system

disorders

Anaphylaxis

Metabolism and

nutrition

disorders

Hyponatraemia

Lactic acidosis*

Psychiatric

disorders

Insomnia

Nervous system

disorders

Headache, taste

perversion (metallic

taste), dizziness

Convulsions*,

hypoaesthesia,

paraesthesia

Serotonin syndrome**,

peripheral neuropathy*

Eye disorders

Blurred vision*

Changes in visual

field defect*

Optic neuropathy*,

optic neuritis*, loss of

vision*, changes in

visual acuity*, changes

in colour vision*

Ear and labyrinth

disorders

Tinnitus

Cardiac

disorders

Arrhythmia

(tachycardia)

Vascular

disorders

Hypertension

Transient ischaemic

attacks, phlebitis,

thrombophlebitis

Gastrointestinal

disorders

Diarrhoea, nausea,

vomiting, localised

or general

abdominal pain,

constipation,

dyspepsia.

Pancreatitis,

gastritis, abdominal

distension, dry

mouth, glossitis,

loose stools,

stomatitis, tongue

discolouration or

disorder

Superficial tooth

discolouration

System Organ

Class

Common (>1/100

to <1/10)

Uncommon

(>1/1,000 to <1/100)

Rare

(1/10,000 to

<1/1,000)

Frequency not known

(cannot be estimated

from available data)

Hepatobiliary

disorders

Abnormal liver

function test;

increased AST,

ALT or alkaline

phosphatase

Increased total

bilirubin

Skin and

subcutaneous

tissue disorders

Pruritus, rash

Urticaria, dermatitis,

diaphoresis

Bullous disorders such

as those described as

Stevens-Johnson

syndrome and toxic

epidermal necrolysis,

angioedema, alopecia

Renal and

urinary disorders

Increased BUN

Renal failure,

increased creatinine,

polyuria

Reproductive

system and

breast disorders

Vulvovaginal

disorder

General

disorders and

administration

site conditions

Fever, localised

pain

Chills, fatigue,

increased thirst

Investigations

Chemistry

Increased LDH,

creatine kinase,

lipase, amylase or

non fasting glucose.

Decreased total

protein, albumin,

sodium or calcium.

Increased or

decreased

potassium or

bicarbonate.

Haematology

Increased

neutrophils or

eosinophils.

Decreased

haemoglobin,

haematocrit or red

blood cell count.

Increased or

decreased platelet

or white blood cell

counts.

Chemistry Increased

sodium or calcium.

Decreased non

fasting glucose.

Increased or

decreased chloride.

Haematology

Increased

reticulocyte count.

Decreased

neutrophils.

* See section 4.4.

** See sections 4.3 and 4.5.

† See below.

The following adverse reactions to linezolid were considered to be serious in rare cases: localised

abdominal pain, transient ischaemic attacks and hypertension.

†In controlled clinical trials where linezolid was administered for up to 28 days, less than 0.1% of the

patients reported anaemia. In a compassionate use program of patients with life-threatening infections and

underlying co-morbidities, the percentage of patients who developed anaemia when receiving linezolid

for < 28 days was 2.5% (33/1326) as compared with 12.3% (53/430) when treated for >28 days. The

proportion of cases reporting drug-related serious anaemia and requiring blood transfusion was 9% (3/33)

in patients treated for < 28 days and 15% (8/53) in those treated for >28 days.

Paediatric population

Safety data from clinical studies based on more than 500 paediatric patients (from birth to 17 years) do

not indicate that the safety profile of linezolid for paediatric patients differs from that for adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at

www.mhra.gov.uk/yellowcard.

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.

Signs of toxicity in rats following doses of 3,000 mg/kg/day linezolid were decreased activity and ataxia

whilst dogs treated with 2,000 mg/kg/day experienced vomiting and tremors.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other antibacterials. ATC code: J01XX08

General properties

Linezolid is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the

oxazolidinones. It has in vitro activity against aerobic Gram positive bacteria and anaerobic micro-

organisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action.

Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the

formation of a functional 70S initiation complex which is an essential component of the translation

process.

The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2

hours. When measured in animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus

aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic

parameter for efficacy was the time for which the linezolid plasma level exceeded the minimum

inhibitory concentration (MIC) for the infecting organism.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on

Antimicrobial Susceptibility Testing (EUCAST) for staphylococci and enterococci are Susceptible ≤

4mg/L and Resistant >4 mg/L. For streptococci (including S. pneumoniae) the breakpoints are

Susceptible ≤ 2 mg/L and Resistant >4 mg/L.

Non-species related MIC breakpoints are susceptible ≤ 2 mg/L and Resistant > 4 mg/L. Non-species

related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC

distributions of specific species. They are for use only for organisms that have not been given a specific

breakpoint and not for those species where susceptibility testing is not recommended.

Susceptibility

local information on resistance is desirable, particularly when treating severe infections. As necessary,

expert advice should be sought when local prevalence of resistance is such that the utility of the agent in

at least some types of infections is questionable.

Category

Susceptible organisms

Gram positive aerobes:

Enterococcus faecalis

Enterococcus faecium*

Staphylococcus aureus*

Coagulase negative staphylococci

Streptococcus agalactiae*

Streptococcus pneumoniae*

Streptococcus pyogenes*

Group C streptococci

Group G streptococci

Gram positive anaerobes:

Clostridium perfringens

Peptostreptococcus anaerobius

Peptostreptococcus species

Resistant organisms

Haemophilus influenzae

Moraxella catarrhalis

Neisseria species

Enterobacteriaceae

Pseudomonas species

*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications

Whereas linezolid shows some in vitro activity against Legionella, Chlamydia pneumoniae and

Mycoplasma pneumoniae, there are insufficient data to demonstrate clinical efficacy.

Resistance

Cross resistance

Linezolid's mechanism of action differs from those of other antibiotic classes. In vitro studies with

clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and

penicillin- and erythromycin-resistant streptococci) indicate that linezolid is usually active against

organisms which are resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

As documented with other antibiotics when used in patients with difficult to treat infections and/or for

prolonged periods, emergent decreases in susceptibility have been observed with linezolid. Resistance to

linezolid has been reported in enterococci, Staphylococcus aureus and coagulase negative staphylococci.

This generally has been associated with prolonged courses of therapy and the presence of prosthetic

materials or undrained abscesses. When antibiotic-resistant organisms are encountered in the hospital it is

important to emphasise infection control policies.

Information from clinical trials

Studies in the paediatric population

In an open study, the efficacy of linezolid (10 mg/kg q8h) was compared to vancomycin (10-15 mg/kg

q6-24h) in treating infections due to suspected or proven resistant Gram-positive pathogens (including

nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteraemia,

bacteraemia of unknown source, and other infections), in children from birth to 11 years. Clinical cure

rates in the clinically evaluable population were 89.3% (134/150) and 84.5% (60/71) for linezolid and

vancomycin, respectively (95%CI: -4.9, 14.6).

5.2 Pharmacokinetic properties

Linezolid primarily contains (s)-linezolid which is biologically active and is metabolised to form inactive

derivatives.

Absorption

Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are

reached within 2 hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing

in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food

and absorption from the oral suspension is similar to that achieved with the film-coated tablets.

Plasma linezolid C

and C

(mean and [SD]) at steady-state following twice daily intravenous dosing

of 600 mg have been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.

In another study following oral dosing of 600 mg twice daily to steady-state, C

and C

were

determined to be 21.2 [5.8] mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved

by the second day of dosing.

Distribution

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 C

, 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 C

was 0.7:1.0 after multiple linezolid dosing.

Biotransformation

Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation

of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-

142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite

(PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic

process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant. Other minor, inactive

metabolites have been characterised.

Elimination

In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily

excreted under steady-state conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-

142300 (10%). Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each

dose appears as PNU-142586 and PNU-142300, respectively. The elimination half-life of linezolid

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

Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two

primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine

clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some

removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600

mg doses were still considerably higher following dialysis than those observed in patients with normal

renal function or mild to moderate renal insufficiency.

In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma

concentrations of the two major metabolites after several days dosing were about 10 fold those seen in

patients with normal renal function. Peak plasma levels of linezolid were not affected.

The clinical significance of these observations has not been established as limited safety data are currently

available (see sections 4.2 and 4.4).

Hepatic impairment: Limited data indicate that the pharmacokinetics of linezolid, PNU-142300 and

PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class

A or B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (i.e. Child-Pugh

class C) 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 (see sections

4.2 and 4.4).

Paediatric population: There are insufficient data on the safety and efficacy of linezolid in children and

adolescents (< 18 years old) and therefore, use of linezolid in this age group is not recommended (see

section 4.2). Further studies are needed to establish safe and effective dosage recommendations.

Pharmacokinetic studies indicate that after single and multiple doses in children (1 week to 12 years),

linezolid clearance (based on kg body weight) was greater in paediatric patients than in adults, but

decreased with increasing age.

In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure

approximating to that achieved with 600 mg twice daily in adults.

In neonates up to 1 week of age, the systemic clearance of linezolid (based on kg body weight) increases

rapidly in the first week of life. Therefore, neonates given 10 mg/kg every 8 hours daily will have the

greatest systemic exposure on the first day after delivery. However, excessive accumulation is not

expected with this dosage regimen during the first week of life as clearance increases rapidly over that

period.

In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to that in adults following a

600mg dose. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure

to that observed in adults receiving the same dosage.

In paediatric patients with ventriculoperitoneal shunts who were administered linezolid 10 mg/kg either

12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) linezolid concentrations were observed

following either single or multiple dosing of linezolid. Therapeutic concentrations were not consistently

achieved or maintained in the CSF. Therefore, the use of linezolid for the empirical treatment of

paediatric patients with central nervous system infections is not recommended.

Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and

over.

Female patients: 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 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

Linezolid decreased fertility and reproductive performance of male rats at exposure levels approximately

equal to those in humans. In sexually mature animals these effects were reversible. However, these effects

did not reverse in juvenile animals treated with linezolid for nearly the entire period of sexual maturation.

Abnormal sperm morphology in testis of adult male rats, and epithelial cell hypertrophy and hyperplasia

in the epididymis were noted. Linezolid appeared to affect the maturation of rat spermatozoa.

Supplementation of testosterone had no effect on linezolid-mediated fertility effects. Epididymal

hypertrophy was not observed in dogs treated for 1 month, although changes in the weights of prostate,

testes and epididymis were apparent.

Reproductive toxicity studies in mice and rats showed no evidence of a teratogenic effect at exposure

levels 4 times or equivalent, respectively, to those in humans. The same linezolid concentrations caused

maternal toxicity in mice and were related to increased embryo death including total litter loss, decreased

foetal body weight and an exacerbation of the normal genetic predisposition to sternal variations in the

strain of mice. In rats, slight maternal toxicity was noted at exposures lower than clinical exposures. Mild

foetal toxicity, manifested as decreased foetal body weights, reduced ossification of sternebrae, reduced

pup survival and mild maturational delays were noted. When mated, these same pups showed evidence of

a reversible dose-related increase in pre-implantation loss with a corresponding decrease in fertility. In

rabbits, reduced foetal body weight occurred only in the presence of maternal toxicity (clinical signs,

reduced body weight gain and food consumption) at low exposure levels 0.06 times compared to the

expected human exposure based on AUCs. The species is known to be sensitive to the effects of

antibiotics.

Linezolid and its metabolites are excreted into the milk of lactating rats and the concentrations observed

were higher than those in maternal plasma.

Linezolid produced reversible myelosuppression in rats and dogs.

In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of

sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed

in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-

fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate

optic nerve degeneration was evident in 2 of 3 male rats after 6 months of dosing, but the direct

relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical

distribution. The optic nerve degeneration observed was microscopically comparable to spontaneous

unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common

background change.

Preclinical data, based on conventional studies of repeated-dose toxicity and genotoxicity, revealed no

special hazard for humans beyond those addressed in other sections of this Summary of Product

Characteristics. Carcinogenicity / oncogenicity studies have not been conducted in view of the short

duration of dosing and lack of genotoxicity in the standard battery of studies.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline (E460)

Crospovidone

Hydroxypropylcellulose (E463)

Silica, colloidal anhydrous

Magnesium stearate (E572)

Coating:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

oPA/Al/PVC-Al blister

Boxes containing either 1, 10, 10x1, 20, 30, 50 or 60 tablets, or 100 tablets (for hospital use only).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close,

Potters Bar,

Hertfordshire EN6 1TL,

United Kingdom

8. Marketing authorisation number(s)

PL 04569/1640

9. Date of first authorisation/renewal of the authorisation

19/11/2014

10. Date of revision of the text

11/04/2018

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

Read the complete document

Public Assessment Report

National Procedure

Linezolid 600mg Film-Coated Tablets

(linezolid)

PRODUCT LICENCE NUMBER:

PL 20416/0517

Crescent Pharma Limited.

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

2

LAY SUMMARY

Linezolid 600mg Film-Coated Tablets

(linezolid)

This is a summary of the Public Assessment Report (PAR) for Linezolid 600 Film-coated

Tablets. It explains how this product was assessed and its authorisation recommended, as

well as its conditions of use. It is not intended to provide practical advice on how to use this

product.

This product will be referred to as Linezolid Tablets in this lay summary for ease of reading

For practical information about using Linezolid Tablets, patients should read the package

leaflet or contact their doctor or pharmacist.

What are Linezolid Tablets

and what are they used for?

This application is the same as Linezolid 600 mg Film-Coated Tablets (PL 37222/0036)

which is already authorised.

The Company responsible for Linezolid 600 mg Film-Coated Tablets has agreed that its

scientific data can be used as the basis for the grant of an identical licence for Linezolid

Tablets.

Linezolid Tablets is used in adults to treat pneumonia and some infections in the skin or

under the skin.

How do Linezolid Tablets

work?

Linezolid is an antibiotic of the oxazolidinones group that works by stopping the growth of

certain bacteria (germs) that cause infections.

How are Linezolid Tablets

used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of

administration is Oral (via the mouth).

Use in adults:

The usual dose is one tablet (600mg linezolid) twice daily (every twelve hours). The tablet

should be swallowed whole with a glass of water.

If the patient is on kidney dialysis, they should take Linezolid Tablets after dialysis treatment.

A course of treatment usually lasts 10 to 14 days but can last up to 28 days.

While the patient is taking this medicine, the doctor should perform regular blood

tests to monitor the patient’s blood count.

Use in children:

This medicine is not normally used to treat children and adolescents (under 18 years old).

For further information on how Linezolid Tablets are used, refer to the package leaflet and

Summary of Product Characteristics available on the Medicines and Healthcare products

Regulatory Agency (MHRA) website.

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

3

This medicine can only be obtained with a prescription.

The patient should always take the medicine exactly as their doctor/pharmacist has told them.

The patient should check with their doctor or pharmacist if they are not sure.

What benefits of Linezolid Tablets

have been shown in studies?

Linezolid Tablets are considered identical to the previously authorised product with the same

benefits and risks. No new studies have been provided for Linezolid Tablets, however,

reference is made to the studies for Linezolid 600 mg Film-Coated Tablets.

What are the possible side effects of Linezolid Tablets?

Linezolid Tablets are considered to be identical to the previously authorised product with the

same benefits and risks.

For the full list of all side effects reported with this medicine, see Section 4 of the package

leaflet or the Summary of Product Characteristics (SmPC) available on the MHRA website.

Why were Linezolid Tablets

approved?

The MHRA decided that the benefits of Linezolid Tablets are greater than the risks and

recommended that this medicine is approved for use.

What measures are being taken to ensure the safe and effective use of Linezolid

Tablets?

A Risk Management Plan (RMP) has been developed to ensure that Linezolid Tablets are

used as safely as possible. Based on this plan, safety information has been included in

the SmPC and the package leaflet, including the appropriate precautions to be followed by

healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored and reviewed continuously.

Other information about Linezolid Tablets

A Marketing Authorisation was granted in the UK on 09 July 2019.

The full PAR for Linezolid Tablets follows this summary.

This summary was last updated in August 2019.

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

4

TABLE OF CONTENTS

I.

INTRODUCTION

........................................................................................................ 5

II.

EXPERT REPORT

...................................................................................................... 6

III.

ASSESSOR’S COMMENTS ON THE PRODUCT INFORMATION

................... 6

IV.

QUALITY ASPECTS

.................................................................................................. 6

V.

NON-CLINICAL ASPECTS

...................................................................................... 7

VI.

CLINICAL ASPECTS

................................................................................................. 7

VII.

RISK MANAGEMENT PLAN (RMP)

...................................................................... 7

VIII.

USER CONSULTATION

............................................................................................ 7

IX.

OVERALL CONCLUSION, BENEFIT/RISK AND RECOMMENDATION

...... 8

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

5

I.

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare

products Regulatory Agency (MHRA) considered that the application Linezolid 600mg Film-

Coated Tablets (PL 20416/0517) could be approved.

The product is approved for the following indications:

Nosocomial pneumonia

Community acquired pneumonia

Linezolid is indicated in adults for the treatment of community acquired pneumonia

and nosocomial pneumonia when known or suspected to be caused by susceptible

Gram positive bacteria. In determining whether Linezolid is an appropriate treatment,

the results of microbiological tests or information on the prevalence of resistance to

antibacterial agents among Gram positive bacteria should be taken into consideration.

(See section 5.1 for the appropriate organisms).

Linezolid is not active against infections caused by Gram negative pathogens.

Specific therapy against Gram negative organisms must be initiated concomitantly if

a mixed infection with a Gram negative pathogen is documented or suspected.

Complicated skin and soft tissue infections (see section 4.4 of the SmPC)

Linezolid is indicated in adults for the treatment of complicated skin and soft tissue

infections only when microbiological testing has established that the infection is

known to be caused by susceptible Gram positive bacteria.

Linezolid is not active against infections caused by Gram negative pathogens.

Linezolid should only be used in adults with complicated skin and soft tissue

infections with known or possible co-infection with Gram negative organisms if there

are no alternative treatment options available (see section 4.4). In these circumstances

treatment against Gram negative organisms must be initiated concomitantly.

Linezolid should only be initiated in a hospital environment and after consultation

with a relevant specialist such as a microbiologist or infectious diseases specialist.

Consideration should be given to official guidance on the appropriate use of antibacterial

agents.

Linezolid primarily contains (s)-linezolid which is biologically active and is metabolised to

form inactive derivatives.

Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma

concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid

(oral and intravenous dosing in a crossover study) is complete (approximately 100%).

Absorption is not significantly affected by food and absorption from the oral suspension is

similar to that achieved with the film-coated tablets.

This is a national abridged application submitted under Article 10c of Directive 2001/83/EC,

as amended (an informed consent application). The application cross-refers to the reference

product Linezolid 600 mg Film-Coated Tablets (PL 37222/0036) granted in the UK to the

Marketing Authorisation Holder Hetero Europe S.L., on 13 September 2016.

No new non-clinical or clinical data have been supplied and none are required for this

informed consent application.

Suitable justification has been provided for non-submission of an Environmental Risk

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

6

Assessment (ERA). As the application is for an identical version of an already authorised

product, no increase in environmental exposure is anticipated and no ERA is required.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice

(GMP) are in place for this product at all sites responsible for the manufacture, assembly and

batch release of this/these product.

A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been

provided with this/these application(s) and are satisfactory.

A Marketing Authorisation was granted on 9 July 2019.

II.

EXPERT REPORT

The applicant cross-refers to the data for Linezolid 600 mg Film-Coated Tablets (PL

37222/0036; Hetero Europe S.L), to which this application is claimed to be identical. This is

acceptable.

III.

ASSESSOR’S COMMENTS ON THE PRODUCT INFORMATION

SUMMARY OF PRODUCT CHARACTERITICS (SmPC)

The SmPC is in line with that for Linezolid 600 mg Film-Coated Tablets (PL 37222/0036),

dated 09/2016.

PATIENT INFORMATION LEAFLET

A leaflet mock-up has been provided which has been aligned with that for Linezolid 600 mg

Film-Coated Tablets (PL 37222/0036), dated for 09/2016. The user test report submitted for

PL 37222/0036 has been provided.

LABEL

Label mock-ups have been provided.

IV.

QUALITY ASPECTS

IV.1

Drug Substance

Drug substance specification

The source of the active substance is in line with the cross-reference product. The proposed

drug substance specification is consistent with the details registered for the cross-reference

product.

IV.2.

Drug Product

Name

The product has been named in line with current requirements.

Strength, pharmaceutical form, route of administration, container and pack sizes

Linezolid 600 mg Film-Coated Tablets are available in Alu-Alu blisters containing 1, 10, 20,

30, 50, 60, 100, 200 film-coated tablets and HDPE bottles containing 20 and 100 film-coated

tablets.

The appearance of the product is identical to that of the cross-reference product.

The proposed shelf life of the product is 30 months, in use shelf-life after first opening the

HDPE bottles is 30 days with no special storage conditions.

The proposed packaging, shelf life and storage conditions are consistent with the details

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

7

registered for the reference product.

Legal status

Prescription only medicine (POM

Manufacturers

The proposed manufacturing site are consistent with the details registered for the cross-

reference product and evidence of Good Manufacturing Practice (GMP) compliance has been

provided.

Qualitative and quantitative compositions

The composition of the proposed product is consistent with the details registered for the

cross-reference product.

Manufacturing process & control of critical steps

The proposed manufacturing processes and process controls are consistent with the details

registered for the reference product and the maximum batch size is stated.

Finished product release/shelf life specifications

The proposed finished product specification is in line with the details registered for the cross-

reference product.

TSE Compliance

With the exception of lactose monohydrate, no excipients of animal or human origin are used

in the final products.

The supplier of lactose monohydrate has confirmed that it is sourced from healthy animals

under the same conditions as milk for human consumption.

Confirmation has been given that the magnesium stearate used in the tablets is of vegetable

origin.

This product does not contain or consist of genetically modified organisms (GMO).

V.

NON-CLINICAL ASPECTS

As this application is submitted under Article 10c of Directive 2001/83/EC, as amended, (as

an informed consent application) no new non-clinical data have been supplied and none are

required.

VI.

CLINICAL ASPECTS

As this application is submitted under Article 10c of Directive 2001/83/EC, as amended, (as

an informed consent application) no new clinical data have been supplied and none are

required.

VII.

RISK MANAGEMENT PLAN (RMP)

The applicant has submitted an RMP, in accordance with the requirements of Directive

2001/83/EC, as amended. The applicant proposes only routine pharmacovigilance and routine

risk minimisation measures for all safety concerns. This is acceptable.

VIII.

USER CONSULTATION

A user consultation with target patient groups on the Patient Information Leaflet (PIL) has

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

8

been performed on the basis of a bridging report making reference to Linezolid 600 mg Film-

coated Tablets (PL 37222/0036; Hetero Europe S.L.). The bridging report submitted by the

applicant is acceptable.

IX.

OVERALL CONCLUSION, BENEFIT/RISK AND RECOMMENDATION

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns

have been identified. The applicant’s product is identical to the cross-reference product. The

benefit/risk balance is, therefore, considered to be the same as for the cross-reference product

and positive.

The Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

labelling are satisfactory, in line with current guidelines and consistent with the cross-

reference product.

In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs

and PILs for these products are available on the MHRA website.

Representative copies of the labels at the time of UK licensing are provided below.

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

9

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

10

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

11

PAR Linezolid 600mg Film-Coated Tablets

PL 20416/0517

12

TABLE OF CONTENT OF THE PAR UPDATE

Steps taken after the initial procedure with an influence on the Public Assessment Report

(non-safety variations of clinical significance).

Please note that only non-safety variations of clinical significance are recorded below and in

the annexes to this PAR. The assessment of safety variations where significant changes are

made are recorded on the MHRA website or European Medicines Agency (EMA) website.

Minor changes to the marketing authorisation are recorded in the current SmPC and/or PIL

available on the MHRA website.

Application

type

Scope

Product

information

affected

Date of grant

Outcome

Assessment

report

attached

Y/N

Similar products

Search alerts related to this product

View documents history

Share this information