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LINEZOLID KRKA 2MG/ML SOLUTION FOR INFUSION

Active substance(s): LINEZOLID

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NA LINEZOLID KRKA GB prva stran

Package leaflet: Information for the user

Linezolid Krka 2 mg/ml

known as SSRI’s (see section 2).

solution for infusion
Linezolid

Read all of this leaflet carefully before this medicinal product is
given to you 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 or
nurse.
• If you get any side effects, talk to your doctor or pharmacist or nurse.
This includes any possible side effects not listed in this leaflet. See
section 4.
What is in this leaflet
1. What Linezolid Krka is and what it is used for
2. What you need to know before you are treated with Linezolid Krka
3. How Linezolid Krka is given
4. Possible side effects
5. How to store Linezolid Krka
6. Contents of the pack and other information

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Linezolid Krka

1. What Linezolid Krka is and what it is used for

Linezolid

Linezolid Krka is an antibiotic of the oxazolidinones group that works by
stopping the growth of certain bacteria (germs) that cause infections in
adults. It is used to treat pneumonia and some infections in the skin or
under the skin. Your doctor will have decided if Linezolid Krka is suitable
to treat your infection.

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2. What you need to know before you are treated with
Linezolid Krka

Linezolid Krka
Linezolid

vizualna koda

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173 mm ± 0,5 mm

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You should not be treated with Linezolid Krka:
• 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 medications
may be used to treat depression or Parkinson’s disease.
• if you are breast-feeding. This is because Linezolid Krka passes into
breast milk and could affect the baby.
Warnings and precautions
Talk to your doctor or pharmacist or nurse before you are treated with
Linezolid Krka.
Linezolid Krka 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, whether or not you are taking
medicines for this?
• 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 problems?
• Are you taking any of the following medicines?
-- decongestant, cold or flu remedies containing pseudoephedrine or
phenylpropanolamine
-- medicines used to treat asthma such as salbutamol, terbutaline,
fenoterol
-- antidepressants known as tricyclics or SSRIs (selective serotonin
reuptake inhibitors) for example amitriptyline, cipramil, 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

-- medicines used to treat moderate to severe pain, such as pethidine
-- medicines used to treat anxiety disorders, such as buspirone
-- an antibiotic called rifampicin
Take special care with Linezolid Krka
Tell your doctor before you are treated with this medicine 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 kidney problems particularly if you are on dialysis
• have diarrhoea
Tell your doctor immediately if during treatment you suffer from:
• problems with your vision such as blurred vision, changes in colour
vision, difficulty in seeing detail or if your field of vision becomes
restricted.
• loss of sensitivity in your arms or legs or a sensation of tingling or
pricking in your arms or legs.
• You may develop diarrhoea while taking or after taking antibiotics,
including Linezolid Krka. If this becomes severe or persistent or you
notice that your stools contains blood or mucus, you should stop taking
Linezolid Krka immediately and consult your doctor. In this situation, you
should not take medicines that stop or slow bowel movement.
• recurrent nausea or vomiting, abdominal pain or rapid breathing.
Other medicines and Linezolid Krka
There is a risk that Linezolid Krka 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 Krka must not be taken if you
are already taking these medicines or have taken them recently (see also
Section 2 above ‘You should not be treated with Linezolid Krka ’).
• 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 the following medicines. Your doctor
may still decide to give you Linezolid Krka, 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, cipramil, 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.
• Medicines used to treat moderate to severe pain, such as pethidine.
• Medicines used to treat anxiety disorders, such as buspirone.
• Medicines that stop blood clotting, such as warfarin.
Tell your doctor or pharmacist if you are taking or have recently taken or
might take any other medicines.
Linezolid Krka with food and drink
• You can take Linezolid Krka either before, during or after a meal.
• 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 Linezolid Krka may react with a
substance called tyramine which is naturally present in some foods. This
interaction may cause an increase in your blood pressure.
• If you develop a throbbing headache after eating or drinking, tell your
doctor or pharmacist immediately.
Pregnancy and breast-feeding and fertility
The effect of Linezolid Krka in pregnant women is not known. Therefore, it

should not be taken in pregnancy unless advised by your doctor. If you
are pregnant, think you may be pregnant or are planning to have a baby,
ask your doctor or pharmacist for advice before taking this medicine.
You should not breast-feed when taking Linezolid Krka because it passes
into breast milk and could affect the baby.

Numbness, tingling or blurred vision have been reported by patients who
have been given Linezolid Krka for more than 28 days. If you experience
difficulties with your vision you should consult your doctor as soon as
possible.

Driving and using machines
Linezolid Krka 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.

Common side effects (may affect up to 1 in 10 people):
• Fungal infections especially vaginal or oral “thrush”
• Headache
• Metallic taste in the mouth
• Diarrhoea, nausea or vomiting
• Changes in some blood test results including those measuring your
kidney or liver function or blood sugar levels
• Unexplained bleeding or bruising, which may be due to changes in the
numbers of certain cells in the blood which may affect blood clotting or
lead to anaemia
• Difficulty in sleeping
• Increased blood pressure
• Anaemia (low red blood cell)
• Changes in numbers of certain cells in the blood which may affect your
ability to fight infection
• Skin rash
• Itching skin
• Dizziness
• Localised or general abdominal pain
• Constipation
• Indigestion
• Localised pain
• Fever

Linezolid Krka contains glucose.
300 ml of solution for infusion contains 13.7 g glucose. This should be
taken into account in patients with diabetes mellitus.
Linezolid Krka contains sodium.
300 ml of solution for infusion contains 114 mg sodium (5 mmol). To be
taken into consideration by patients on a controlled sodium diet.

3. How Linezolid Krka is given
Adults
This medicine will be given to you through a drip (by infusion into a vein)
by a doctor or healthcare professional. The usual dose for adults (18
years and older) is 300 ml (600 mg linezolid) twice daily which is given
directly into the blood stream (intravenously) by a drip over a period of 30
to 120 minutes.
If you are on kidney dialysis, you should be given Linezolid Krka 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 Krka, your doctor should perform regular
blood tests to monitor your blood count.
Your doctor should monitor your eyesight if you take Linezolid Krka for
more than 28 days.
Use in children and adolescents
Linezolid Krka is not normally used to treat children and adolescents
(under 18 years old).
If you receive more Linezolid Krka than you should
If you are concerned that you may have been given too much Linezolid
Krka, tell your doctor or a nurse at once.
If you miss a dose of Linezolid Krka
As you will be given this medicine under close supervision, it is very
unlikely that you will miss a dose. If you think that you have missed a dose
of treatment, tell a doctor or nurse at once.
If you have any further questions on the use of this medicine, ask your
doctor, pharmacist or nurse.

4. Possible side effects
Like all medicines, this medicine can cause side effects, although not
everybody gets them.
Tell your doctor, nurse or pharmacist immediately if you notice any of
these side effects during your treatment with Linezolid Krka:
• skin reactions such as red sore skin and flaking (dermatitis), rash,
itching, or swelling, particularly around the face and neck. This may be
the sign of an allergic reaction and it may be necessary for you to stop
taking Linezolid Krka.
• problems with your vision such as blurred vision, changes in colour
vision, difficulty in seeing detail or if your field of vision becomes
restricted.
• severe diarrhoea containing blood and/or mucus (antibiotic associated
colitis including pseudomembranous colitis), which in rare circumstances
may develop into complications that are life-threatening.
• recurrent nausea or vomiting, abdominal pain or rapid breathing.
• fits or seizures have been reported with Linezolid Krka. You should let
your doctor know if you experience agitation, confusion, delirium, rigidity,
tremor, incoordination and seizure while also taking antidepressants

Other side effects include:

Uncommon side effects (may affect up to 1 in 100 people):
• Inflammation of the vagina or genital area in women
• Sensations such as tingling or feeling numb
• Blurred vision
• “Ringing” in the ears (tinnitus)
• Inflammation of the veins
• Dry or sore mouth, swollen, sore, or discoloured tongue
• Pain at and around the place where the infusion (drip) was given
• Inflammation of the veins (including where the infusion (drip) was given)
• A need to urinate more often
• Chills
• Feeling tired or thirsty
• Inflammation of the pancreas
• Increased sweating
• Changes in proteins, salts or enzymes in the blood which measure
kidney or liver function.
• Convulsions
• Hyponatraemia (low blood sodium levels)
• Kidney failure
• Reduction in platelets
• Abdominal bloating
• 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).
• Injection site pain
• Inflammation of the skin
• Increase in creatinine
• Stomach pain
• Changes in heart rate (e.g. increase rate)
Rare side effects (may affect up to 1 in 1000 people):
• Restricted field of vision
• Superficial tooth discolouration, removable with professional dental
cleaning (manual descaling)
The following side effects have also been reported (frequency cannot
be estimated from the available data):
• Serotonin syndrome (symptoms include fast heart rate, confusion,
abnormal sweating, hallucinations, involuntary movements chills and
shivering)
• Lactic acidosis (symptoms include recurrent nausea and vomiting,
abdominal pain, rapid breathing)
• Severe skin disorders
• Sideroblastic anaemia (a type of anaemia (low red blood cells))

• Alopecia (hair loss)
• Changes in colour vision or difficulty in seeing detail
• Decrease of the blood cell count
• Weakness and/or sensory changes
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist or nurse. This
includes any possible side effects not listed in this leaflet. You can also
report side effects directly via via Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the
safety of this medicine.

5. How to store Linezolid Krka
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the
packaging after EXP. The expiry date refers to the last day of that month.
Do not store above 30°C.
Store in the original package in order to protect from light.
After opening: Chemical and physical in-use stability has been
demonstrated for 24 hours at room temperature in primary bag after
removal of the secondary pack (pouch). From a microbiological point of
view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of
the user.
Do not use this medicine if you notice that solution is not clear, colourless
to yellow or to yellowish-brown.
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 Krka contains
• The active substance is linezolid. 1 ml of solution for infusion contains 2
mg linezolid. Each 300 ml infusion bag contains 600 mg linezolid.
• The other ingredients are glucose monohydrate, sodium citrate
dihydrate, citric acid anhydrous, hydrochloric acid (for pH-adjustment),
sodium hydroxide (for pH-adjustment) and water for injections. See
section 2 “Linezolid Krka contains glucose and sodium.”
What Linezolid Krka looks like and contents of the pack
Clear colourless to yellow or to yellowish-brown solution (pH: 4.6 – 5.2,
osmolality: 270 mOsmol/kg – 320 mOsmol/kg).
Linezolid solution for infusion:
Primary packaging:
multilayer polyolefin plastic bag (300 ml) with multilayer polyolefin plastic
port tube and polyolefin twist off connector.
Secondary packaging:
Overpouch bag made of multilayer film. Film layers of bag from outside to
inside: polyester, aluminium, polyester, propylene, 1 and 10 in a box.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
This leaflet was last revised in
-------------------------------------------------------------------------------------------------The following information is intended for healthcare professionals only:
Linezolid Krka 2 mg/ml solution for infusion
Linezolid
IMPORTANT: Refer to Summary of Product Characteristics before
prescribing.
Linezolid is not active against infections caused by Gram negative
pathogens. Specific therapy against Gram negative organisms must be
initiated concomitantly if co-infection with a Gram negative pathogen is
documented or suspected.
Description
For single use only. The bag holds 300 ml solution and is packaged in a
box. Each box contains 1 or 10 infusion bags.
Linezolid Krka 2 mg/ml solution for infusion contains linezolid 2 mg/ml in a
clear, colourless to yellow or to yellowish-brown solution. Other
ingredients are glucose monohydrate, sodium citrate dihydrate, citric acid

anhydrous, hydrochloric acid, sodium hydroxide and water for injection.
Dosage and method of administration
Linezolid should only be initiated in a hospital environment and after
consultation with a relevant specialist such as a microbiologist or an
infectious diseases specialist.
Patients who commence treatment on the parenteral formulation may be
switched to either oral presentation when clinically indicated. In such
circumstances, no dose adjustment is required as linezolid has an oral
bioavailability of approximately 100 %.
The solution for infusion should be administered over a period of 30 to
120 minutes.
The recommended linezolid dosage should be administered IV twice daily.
Recommended dosage and duration 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 have not yet been established for treatment periods longer
than 28 days.
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
Nosocomial
pneumonia
Community acquired
pneumonia
Complicated skin and
soft tissue infections

Dosage and route
for twice daily
administration

Duration of treatment

600 mg twice daily

600 mg twice daily

10-14 Consecutive
Days

Paediatric population: There are insufficient data on the
pharmacokinetics, safety and efficacy of linezolid in children and
adolescents (< 18 years old) to establish dosage recommendations.
Therefore, until further data are available, use of linezolid in this age
group is not recommended.
Elderly patients: No dose adjustment is required.
Patients with renal insufficiency: No dose adjustment is required.
Patients with severe renal insufficiency (i.e. CLCR < 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 Krka 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).
Patients with hepatic insufficiency: Patients with mild to moderate
hepatic insufficiency (Child-Pugh class A or B): No dose adjustment is
required.
Patients with severe hepatic insufficiency (Child-Pugh class C): As
linezolid is metabolised by a non-enzymatic process, impairment of
hepatic function would not be expected to significantly alter its metabolism
and, therefore, no dose adjustment is recommended. However, there are

no pharmacokinetic data and limited clinical experience of linezolid in
patients with severe hepatic insufficiency. Linezolid should be used with
special caution in patients with severe hepatic insufficiency and only when
the anticipated benefit is considered to outweigh the theoretical risk.
Contraindications
Hypersensitivity to linezolid or to any of the excipients.
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 drug.
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, 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. adrenaline /
epinephrine, noradrenaline / norepinephrine), dopaminergic agents (e.g.
dopamine, dobutamine), pethidine or buspirone.
Breast feeding should be discontinued prior to and throughout
administration.
Special warnings and precautions for use
Myelosuppression
Myelosuppression (including anaemia, leucopenia, 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

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NA LINEZOLID KRKA GB druga stran

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. 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 antibioticassociated 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 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.
Use with tyramine-rich foods
Patients should be advised against consuming large amounts of tyramine
rich foods.
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 nonsusceptible 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.
It is recommended that linezolid should be given to patients with severe
hepatic insufficiency only when the perceived benefit outweighs the
theoretical risk.
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.
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.
Excipients
300 ml of the solution contains 13.7 g glucose. This should be
taken into account in patients with diabetes mellitus.
300 ml of the solution also contains 114 mg sodium (5 mmol). The sodium
content should be taken into consideration by patients on a controlled
sodium diet.
Interactions
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.
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 mm Hg, compared with 11-15 mm Hg
increases with linezolid alone, 14-18 mm Hg with either pseudoephedrine
or phenylpropanolamine alone and 8-11 mm Hg 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 coadministration is contraindicated, management of patients for whom
treatment with linezolid and serotonergic agents is essential, is described
in special warnings and precautions for use.
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 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.
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.
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. 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, breastfeeding should be discontinued prior to
and throughout administration.
Fertility
In animal studies, linezolid caused a reduction in fertility.
Effects on ability to drive and use machines
Patients should be warned about the potential for dizziness or symptoms
of visual impairment whilst receiving linezolid and should be advised not
to drive or operate machinery if any of these symptoms occurs.
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); Not known (cannot be
estimated from the available data)

System Organ Class
Infections and
infestations

Common
(≥1/100 to <1/10)
candidiasis, oral
candidiasis, vaginal
candidiasis, fungal
infections

Uncommon
(≥1/1,000 to <1/100)
vaginitis

Rare
(≥1/10,000 to <1/1,000)
antibiotic-associated colitis,
including pseudomembranous
colitis*

Blood and the lymphatic
anaemia*†
system disorders
Immune system
disorders
Metabolism and
nutrition disorders
Psychiatric disorders
insomnia
headache, taste
Nervous system
perversion (metallic
disorders
taste), dizziness

leucopenia*, neutropenia,
pancytopenia*
thrombocytopenia*, eosinophilia

Eye disorders
Ear and labyrinth
disorders
Cardiac disorders
Vascular disorders

hypertension

Skin and subcutaneous
pruritus, rash
tissue disorders

Investigations

anaphylaxis
hyponatraemia

lactic acidosis*

convulsions*, hypoaesthesia,
paraesthesia

serotonin syndrome**,
peripheral neuropathy*

blurred vision*

optic neuropathy*, optic
neuritis*, loss of vision*,
changes in visual acuity*,
changes in colour vision*

changes in visual field defect*

increased BUN

pancreatitis, gastritis, abdominal
distention, dry mouth, glossitis,
superficial tooth discolouration
loose stools, stomatitis, tongue
discolouration or disorder
increased total bilirubin

renal failure, increased
creatinine, polyuria
vulvovaginal disorder

fever, localised pain
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.

chills, fatigue, injection site pain,
increased thirst

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, 2.0% 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.
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.

arrhythmia (tachycardia)
transient ischaemic attacks,
phlebitis, thrombophlebitis

urticaria, dermatitis, diaphoresis

* See section ”Special Warnings and precautions for use”.
** See sections ”Contraindications” and ”Interactions”
† See below



myelosuppresion*,
sideroblastic anaemia*

tinnitus

diarrhoea, nausea,
vomiting, localised or
Gastrointestinal
general abdominal
disorders
pain, constipation,
dyspepsia
abnormal liver function
test; increased AST,
Hepato-biliary disorders
ALT or alkaline
phosphatase

Renal and urinary
disorders
Reproductive system
and breast disorders
General disorders and
administration site
conditions

Frequency not known
(cannot be estimated from
available data)

bullous disorders such as
those described as StevensJohnson syndrome and
toxic epidermal necrolysis,
angioedema, alopecia

Instructions for use and handling
For single use only. Remove overwrap only when ready to use, then
check for minute leaks by squeezing the bag firmly. If the bag leaks, do
not use as sterility may be impaired. The solution should be visually
inspected prior to use and only clear solutions, without particles should be
used. Do not use these bags in series connections. Any unused solution
must be discarded. No special requirements for disposal. Any unused
medicinal product or waste material should be disposed of in accordance
with local requirements. Do not reconnect partially used bags.
Linezolid Krka Solution for Infusion is compatible with the following
solutions: 5 % glucose intravenous infusion, 0.9 % sodium chloride
intravenous infusion, Ringer-lactate solution for injection (Hartmann’s
solution for injection).
Incompatibilities
Additives should not be introduced into this solution. If linezolid is to be
given concomitantly with other drugs, each drug should be given
separately in accordance with its own directions for use. Similarly, if the
same intravenous line is to be used for sequential infusion of several
drugs, the line should be flushed prior to and following linezolid
administration with a compatible infusion solution.
Linezolid Solution for Infusion is known to be physically incompatible with
the following compounds: amphotericin B, chlorpromazine hydrochloride,
diazepam, pentamidine isethionate, erythromycin lactobionate, phenytoin
sodium and sulphamethoxazole / trimethoprim. Additionally, it is
chemically incompatible with ceftriaxone sodium.

Chemistry
Increased sodium or calcium.
Decreased non fasting glucose.
Increased or decreased
chloride.
Haematology
Increased reticulocyte count.
Decreased neutrophils.

Shelf life
2 years
After opening: Chemical and physical in-use stability has been
demonstrated for 24 hours at room temperature in primary bag after
removal of the secondary pack (pouch). From a microbiological point of
view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of
the user.
Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light.

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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