LINEZOLID 2 mg /Ml Infusion Solution

Зміст інструкції

1. Linezolid Krka 2 mg/ml solution for infusion
   1. What is Linezolid Krka and what it is used for
   2. What you need to know before you take Linezolid Krka
   3. How to take Linezolid Krka
   4. Possible side effects
   5. How to store Linezolid Krka
   6. Contents of the pack and other information

Linezolid Krka 2 mg/ml solution for infusion

Linezolid

Generic medicine

Read this leaflet carefully before you start to use this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

• 1. What Linezolid Krka is and what it is used for
• 2. What you need to know before you are given 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

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

Linezolid Krka is an antibiotic of the oxazolidinone group that works by blocking the growth of
some bacteria (germs) that cause infections in adults. It is used for the treatment of
pneumonia and some skin or subcutaneous infections. The doctor will decide if Linezolid Krka is suitable
for the treatment of your infection.

2. What you need to know before you take Linezolid Krka

You must 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 in the last 2 weeks any medicine known as monoamine oxidase inhibitors (MAOIs, e.g. phenelzine, isocarboxazide, selegiline, moclobemide). These medicines can be used for the treatment of depression or Parkinson's disease.
• if you are breastfeeding, as Linezolid Krka passes into breast milk and could have effects on your baby.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Linezolid Krka.
Linezolid Krka may not be suitable for you if the answer to any of the following questions is yes.
In this case, talk to your doctor as they may need to check your overall health and your blood
pressure before and during treatment, or they may decide that another treatment is better for you.
Ask your doctor if you are not sure if these categories apply to you.

• Do you have high blood pressure, even if you are taking medication for this condition?
• Have you been diagnosed with an overactive thyroid?
• Do you have a tumor of the adrenal glands (pheochromocytoma) or a carcinoid syndrome (caused by tumors of the hormonal system with symptoms such as diarrhea, skin flushing, shortness of breath)?
• Do you suffer from manic depression, schizoaffective disorder, mental confusion or other mental health problems?
• Are you taking any of the following medicines?
• decongestant medicines for colds or flu containing pseudoephedrine or phenylpropanolamine
• medicines used in the treatment of asthma such as salbutamol, terbutaline, fenoterol
• antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors) such as 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 severe and sudden allergic reactions such as adrenaline (epinephrine)
• medicines that increase blood pressure, such as norepinephrine (noradrenaline), 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

Pay particular attention with Linezolid Krka
Talk to your doctor before taking this medicine if:

• you bleed and bruise easily
• you are anemic (have a low number of red blood cells)
• you tend to develop infections
• you have a history of seizures
• you have problems with your liver or kidneys, especially if you are on dialysis
• you have diarrhea

Tell your doctor immediately if you experience:

• problems with your vision such as blurred vision, altered color vision, difficulty seeing details, or if your field of vision becomes restricted.
• loss of sensation in your arms or legs or a tingling or prickling sensation in your arms or legs
• you may develop diarrhea during or after taking antibiotics, including Linezolid Krka. If this becomes severe or persistent or if you notice blood or mucus in your stools, you should immediately stop taking Linezolid Krka and consult your doctor. In this situation, you should not take medicines that block or slow down bowel movements.
• recurring nausea or vomiting, abdominal pain or excessive breathing.

Other medicines and Linezolid Krka
There is a risk that Linezolid Krka may sometimes interact with certain medicines causing
undesirable effects such as changes in blood pressure, temperature or heart rate.

Tell your doctor if you are taking or have taken in the last 2 weeksthe following medicines
because Linezolid Krka must notbe taken if you are already taking these medicines or have taken them recently. (See also section 2 above “You must not be treated with Linezolid Krka”).

• Monoamine oxidase inhibitors (MAOIs, e.g. phenelzine, isocarboxazide, selegiline, moclobemide). These medicines can be used for the treatment of depression or Parkinson's disease.

Also tell your doctor if you are taking the following medicines. The doctor may still decide to
prescribe Linezolid Krka, but they will need to check your overall health and your
blood pressure before and during treatment. In other cases, the doctor may decide that another treatment is better for you.

• Decongestant remedies for colds or flu containing pseudoephedrine or phenylpropanolamine.
• Some medicines used in the treatment of 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 severe and sudden allergic reactions such as adrenaline (epinephrine).
• Medicines that increase blood pressure, such as norepinephrine (noradrenaline), 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 block blood clotting such as warfarin. Tell your doctor or pharmacist if you are taking, have recently taken or may take any other medicine.

Linezolid Krka with food and drink

• You can take Linezolid Krka before, during or after a meal.
• Avoid eating large amounts of aged cheese, yeast extracts or soybean extracts, such as soy sauce, and drinking alcohol, especially draft beer and wine. This is because Linezolid Krka can react with a substance called tyramine which is naturally present in some foods causing an increase in blood pressure.
• If you develop a severe headache after eating or drinking, tell your doctor or pharmacist immediately.

Pregnancy, breastfeeding and fertility
The effect of Linezolid Krka in pregnant women is not known. Therefore, it should not be taken during
pregnancy unless recommended by your doctor. If you are pregnant, suspect you are or are
planning a pregnancy, ask your doctor or pharmacist for advice before taking this
medicine.
Do not breastfeed while taking Linezolid Krka as the medicine can pass into
breast milk and could have effects on the baby.

Driving and operating machinery
Linezolid Krka can cause dizziness or problems with your vision. If this happens, do not drive vehicles and
do not use machinery. Remember that if you do not feel well, your ability to drive or operate
machinery may be affected.

Linezolid Krka contains glucose
300 ml of infusion solution contains 13.7 g of glucose. This must be taken into
consideration in patients with diabetes mellitus.

Linezolid Krka contains sodium
300 ml of infusion solution contains 114 mg of sodium (5 mmol). This must be taken into
consideration in patients on a sodium-controlled diet.

3. How to take Linezolid Krka

Adults
The medicine will be administered to you through an intravenous infusion (into a vein) by a doctor or a
healthcare professional. The usual dose for adults (18 years and over) is 300 ml (600 mg of linezolid) twice
a day, which is administered directly into the bloodstream (intravenously) via an infusion for a period of 30 to 120 minutes.
If you are undergoing renal dialysis, you should take Linezolid Krka after dialysis.
A treatment cycle usually lasts from 10 to 14 days but may last up to 28 days. The safety and
efficacy of this medicine have not been established for treatment periods longer than 28 days. The
doctor will decide how long you should be treated.
During treatment with Linezolid Krka, the doctor will perform regular blood tests to monitor
your blood cell count.
If you take Linezolid Krka for more than 28 days, the doctor will monitor your vision.

Use in children and adolescents
Normally Linezolid Krka is not used for the treatment of children and adolescents (under
18 years of age).

If you take more Linezolid Krka than you should
If you are concerned that you have been given too much Linezolid Krka, inform your doctor or pharmacist immediately.

If you forget to take Linezolid Krka
Since the medicine will be administered under strict supervision, it is very unlikely that a dose will be
forgotten. If you think you have missed a dose of treatment, inform your doctor or
nurse immediately.
If you have any doubts about 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 immediatelyif you notice any of these side effects
during treatment with Linezolid Krka:

• skin reactions such as red and painful skin and scaling (dermatitis), rash, itching or swelling, especially around the face and neck. This may be a sign of an allergic reaction and you may need to stop taking Linezolid Krka.
• vision problems such as blurred vision, changes in colour vision, difficulty seeing details or if your field of vision narrows.
• severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis including pseudomembranous colitis), which in very rare circumstances can progress to life-threatening complications.
• recurring nausea or vomiting, abdominal pain or excessive breathing.
• seizures or convulsions have been reported with Linezolid Krka. You should inform your doctor if you experience agitation, confusion, delirium, rigidity, tremor, lack of coordination and seizures if you are also taking antidepressants known as SSRIs (see section 2).

In patients treated with Linezolid Krka for more than 28 days, numbness, tingling and blurred vision have been reported. If you experience difficulty with your vision you should consult your doctor as soon as possible.

Other side effects include:
Common side effects(may affect up to 1 in 10 people):

• Fungal infections, especially oral or vaginal thrush
• Headache
• Metallic taste in the mouth
• Diarrhoea, nausea and vomiting
• Changes in blood tests measuring kidney or liver function or blood sugar levels
• Unexplained bleeding or bruising which may be due to changes in the number of certain blood cells that can affect blood clotting or lead to anaemia.
• Difficulty sleeping
• Increased blood pressure
• Anaemia (low number of red blood cells)
• Changes in the number of certain blood cells that can affect the ability to fight infections
• Rash
• Itching
• Dizziness
• General or localised abdominal pain
• Constipation
• Indigestion
• Localised pain
• Fever Uncommon side effects(may affect up to 1 in 100 people):
• Inflammation of the vagina or genital area in women
• Sensation of tingling or numbness
• Blurred vision
• “Ringing” in the ears (tinnitus)
• Inflammation of the veins
• Dry or painful mouth, swollen, painful or discoloured tongue
• Pain at the site where the infusion (drip) is given
• Inflammation of the veins (including at the infusion (drip) site)
• 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 measuring kidney or liver function
• Convulsions
• Hyponatremia (low levels of sodium in the blood)
• Kidney failure
• Reduced platelets
• Abdominal bloating
• Transient ischaemic attack (temporary disturbance of blood flow to the brain causing short-term symptoms such as vision loss, weakness of legs and arms, confused speech and loss of consciousness)
• Pain at the injection site
• Skin inflammation
• Increased creatinine
• Stomach ache
• Changes in heart rate (e.g. increased rate)

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

• restricted field of vision
• superficial discolouration of teeth, removable with dental cleaning (manual removal)

The following side effects have also been reported(frequency cannot be estimated on the basis of
available data):

• Serotonin syndrome (symptoms include fast heartbeat, confusion, abnormal sweating, hallucinations, involuntary movements, cold and chills)
• Lactic acidosis (symptoms include recurring nausea and vomiting, abdominal pain, excessive breathing)
• Severe skin disorders
• Sideroblastic anaemia (a type of anaemia (low number of red blood cells))
• Alopecia (hair loss)
• Changes in colour vision, difficulty seeing details
• Reduced number of blood cells
• Weakness and/or sensory changes

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this
leaflet. You can also report side effects directly through the national reporting system at
www.agenziafarmaco.gov.it/it/responsabili. 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 and on the blister after
EXP. The expiry date refers to the last day of that month.
Do not store at a temperature above 30° C.
Store in the original packaging to protect the medicine from light.

After first opening: chemical and physical stabilities have been demonstrated for 24 hours at room
temperature in the bag after removal of the secondary packaging (overwrap). From a
microbiological point of view, the product must be used immediately. If it is not used immediately,
the storage times and conditions prior to use are the responsibility of the user.
Do not use this medicine if you notice that the solution is not clear, from colourless to yellow or brownish-
yellowish.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This 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 of linezolid. Each infusion bag of 300 ml contains 600 mg of linezolid.
• The other components are glucose monohydrate, disodium citrate dihydrate, anhydrous citric acid, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment) and water for injections. See section 2 "Linezolid Krka contains glucose and sodium".

Description of the appearance of Linezolid Krka and contents of the pack
Clear, colourless to yellow-brown solution (pH: 4.6 – 5.2, osmolarity: 270 mOsmol/kg –
320 mOsmol/kg).
Linezolid solution for infusion:
Primary packaging:
multi-layer plastic bag of polyolefins (300ml) with multi-layer plastic tubing of polyolefins and
screw-off polyolefin connector.
Secondary packaging:
Outer overwrap of multi-layer film. Layers of the overwrap film from the outside to the inside: polyester,
aluminium, polyester, propylene, 1 and 10 in a carton.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Local Representative for Italy
Krka Farmaceutici Milano S.r.l. – Italy

This medicinal product is authorised in the Member States of the European Economic Area with the
following names:

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The following information is intended only for healthcare professionals:

Linezolid Krka 2 mg/ml solution for infusion
Linezolid
IMPORTANT: See the Summary of Product Characteristics before prescribing.
Linezolid is not active against infections caused by Gram-negative pathogens. If the presence or
suspicion of Gram-negative pathogens is ascertained, specific therapy for these microorganisms must be
initiated concurrently.

Description
For single use only. The bag contains 300 ml of solution and is contained in a carton.
Each carton contains 1 or 10 infusion bags.
Linezolid Krka 2 mg/ml solution for infusion contains 2mg/ml of clear, colourless to yellow-brown
solution.
The other components are glucose monohydrate, disodium citrate dihydrate, anhydrous citric acid, hydrochloric
acid, sodium hydroxide and water for injections.

Dosage and method of administration
Linezolid must only be administered in a hospital environment and after consultation with specialists
such as microbiologists or infectious disease specialists.
Patients starting treatment with the parenteral formulation may subsequently switch to oral formulations if
clinically appropriate. In such circumstances, no dose adjustment is required as the oral bioavailability of
linezolid is approximately 100%.
The solution for infusion must be administered over a period of 30 to 120 minutes.
The recommended dose should be administered intravenously twice a day.

Recommended dosage and duration of treatment for adults:
The duration of treatment depends on the pathogen, the site of infection and its severity, as well as
the patient’s clinical response.
The following recommendations on therapy duration reflect those adopted in clinical studies.
Shorter treatment regimens may be appropriate for some types of infection but have not been
evaluated in clinical studies.
The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered
for periods longer than 28 days have not been established.
No dosage increase or duration of treatment is required for infections associated with
concomitant bacteraemia.
The recommended dosage for the solution for infusion and the tablets/granules for oral suspension
are identical as reported below:

Paediatric population:Pharmacokinetic, safety and efficacy data for linezolid in children and
adolescents (< 18 years) are insufficient to establish dosage recommendations. Therefore, until
further data are available, the use of linezolid in this age group is not
recommended.

Elderly patients:No dose adjustment is required.

Patients with renal impairment:No dose adjustment is required.
Patients with severe renal impairment (i.e. CL < 30 ml/min): no dose modification is required. Since the clinical significance of increased exposure (up to 10-fold) to the two main
metabolites of linezolid in patients with severe renal impairment is unknown, linezolid must be
used with particular caution in these patients and only when the expected benefit is considered
greater than the theoretical risk.
Since approximately 30% of a linezolid dose is removed in 3 hours of haemodialysis, Linezolid Krka must
be administered after dialysis in patients undergoing this treatment. The main metabolites of
linezolid are eliminated to some extent by haemodialysis, but the concentrations of these
metabolites remain substantially higher after dialysis than those observed in
patients with normal renal function or with mild to moderate renal impairment. Linezolid

must, therefore, be used with particular caution in patients with severe renal impairment
undergoing dialysis, and only when the expected benefit is considered to outweigh the theoretical risk.
There is currently no experience with the administration of linezolid in patients undergoing continuous
ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than
haemodialysis).

Patients with hepatic impairment:Patients with mild to moderate hepatic impairment
(Child-Pugh classification A or B): no dose adjustment is required.
Patients with severe hepatic impairment (Child-Pugh classification C): since linezolid is
metabolised by a non-enzymatic process, it is not expected that altered hepatic function
will significantly alter its metabolism and, consequently, no dose adjustment is recommended. However, pharmacokinetic data and clinical experience with linezolid in patients with
severe hepatic impairment are limited. Linezolid must be used with particular caution in
patients with severe hepatic impairment and only when the expected benefit is considered greater than
the theoretical risk.

Contraindications
Hypersensitivity to linezolid or to any of the other excipients.
Linezolid must not be used in patients who are taking any other medicinal product that
inhibits monoamine oxidase A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or
within two weeks of taking one of these medicinal products.
Unless facilities are available for close monitoring and blood pressure monitoring, linezolid must not be administered to patients with the following clinical conditions or who are taking the following types of drugs concurrently:

• Patients with uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar disorder, schizoaffective disorder, acute confusional states.
• Patients who are taking one of the following medicinal products: serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressor agents (e.g. adrenaline/epinephrine, noradrenaline/norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

Breastfeeding must be interrupted before and during treatment.

Special warnings and precautions for use

Myelosuppression
Cases of myelosuppression (including anemia,
leukopenia, pancytopenia and thrombocytopenia) have been reported in patients treated with linezolid. In cases with a known outcome, altered hematological parameters
returned to levels prior to treatment once linezolid was discontinued. 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 developing blood dyscrasias compared to younger
patients. Thrombocytopenia may occur more commonly in patients with severe renal
insufficiency, whether on dialysis or not. Therefore, careful monitoring of blood
cell counts is recommended in patients with: pre-existing anemia, granulocytopenia or thrombocytopenia; who
are receiving concomitant medications that may decrease hemoglobin levels, suppress the blood
count or exert adverse effects on platelet count or function; with severe renal
insufficiency; undergoing linezolid therapy for more than 10-14 days. In these patients, linezolid must be
administered only when accurate monitoring of hemoglobin levels or blood
count and platelets is possible.
If significant myelosuppression occurs during linezolid therapy, treatment should be discontinued
unless continuation of therapy is considered absolutely
necessary; in such cases, intensive monitoring of blood counts and
adequate treatment measures must be undertaken.
It is also recommended to monitor complete blood counts (including hemoglobin levels, platelets and total and differential white blood cell counts) weekly in patients receiving
linezolid, regardless of baseline blood counts.
During studies for compassionate use, a higher incidence of cases of severe anemia was reported in patients treated with linezolid for periods longer than the maximum recommended duration of 28
days. In these patients, the need for a blood transfusion was more frequent. Cases of anemia requiring
transfusion have also been reported in post-marketing experience, with
a higher incidence in patients undergoing linezolid therapy for more than 28 days.
Cases of sideroblastic anemia have been reported in post-marketing experience. In cases where
the time of onset was known, most patients had received linezolid treatment for
more than 28 days. Most patients showed complete or partial recovery after discontinuation
of linezolid therapy, with or without anemia treatment.

Imbalance in mortality rate in a clinical study on patients with Gram-positive bacterial bloodstream infections

related to the catheter
In an open-label clinical study of critically ill patients with intravascular catheter infections, a
higher mortality rate was observed in patients treated with linezolid compared to those treated with vancomycin, dicloxacillin or oxacillin [78/363 (21.5%) versus 58/363 (16.0%)]. The main
factor influencing the mortality rate was the level of severity of the Gram-positive
infection at baseline. Mortality was similar in patients with infections caused exclusively by Gram-positive
bacteria (odds ratio 0.96; 95% confidence interval: 0.58-1.59), but was significantly higher
(p=0.0162) in the linezolid treatment group in patients who presented with any other
pathogen or no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38-4.46). The
greatest difference occurred during treatment and within 7 days of discontinuation of
therapy. A greater number of patients in the linezolid treatment arm contracted infections
from Gram-negative pathogens during the study, and patients died from Gram-negative pathogen infections and polymicrobial infections. Therefore, in complicated skin and soft tissue infections, linezolid should be used in patients with concomitant infections from Gram-
negative pathogens, known or possible, only when no other therapeutic alternatives are available. In these
circumstances, treatment against Gram-negative pathogens should be started simultaneously.

Antibiotic-associated diarrhea and colitis
Diarrhea associated with
antibiotics and colitis associated with antibiotics, including pseudomembranous colitis and diarrhea associated with

Clostridium difficile, whose severity can range from mild diarrhea to fatal colitis, have been reported with the use of almost all antibiotics, including linezolid. It is therefore important
to consider this diagnosis in patients who develop severe diarrhea during or after use of linezolid.
If antibiotic-associated diarrhea or colitis is suspected or confirmed, the ongoing treatment with antibacterial agents, including linezolid, should be discontinued
and appropriate therapeutic measures should be initiated immediately. Antiperistaltics are
contraindicated in this situation.

Lactic acidosis
Cases of lactic acidosis have been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation, should receive immediate medical
care. If lactic acidosis occurs, the benefits of continuing linezolid therapy should be weighed against the potential risks.

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. Consequently, adverse events such as lactic acidosis, anemia and neuropathy (optic and peripheral) may occur; these events
are more common when the medicine is used for more than 28 days.

Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with the concomitant administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin
re-uptake inhibitors (SSRIs), have been reported. The concomitant administration of linezolid and serotonergic agents is therefore contraindicated except in cases where the concomitant administration
of linezolid and serotonergic agents is essential. In such cases, patients should be closely monitored for any signs and symptoms of serotonin syndrome, such as alterations in
cognitive function, hyperpyrexia, hyperreflexia and lack of coordination. If these
signs and symptoms occur, the doctor should consider interrupting one or both concomitant treatments; if the serotonergic agent is discontinued, withdrawal symptoms may occur.

Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and
optic neuritis, sometimes progressing to vision loss, have been reported in patients treated with linezolid; these cases occurred
mainly in patients treated for periods 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, alterations in color vision, blurred vision or visual field defects. In these cases, prompt examination and, if necessary, referral to an
ophthalmologist is recommended. In cases of taking linezolid for periods longer than the maximum recommended duration of
28 days, regular checks of visual function should be performed in all patients.
If peripheral or optic neuropathy occurs, the continuation of linezolid therapy should be evaluated against the potential risks.
The risk of neuropathy may increase when linezolid is used in patients who are taking or have recently taken antimycobacterial medicines for the treatment of
tuberculosis.

Seizures
Cases of seizures have been reported in patients treated with linezolid. In most
cases, a positive history of seizures or risk factors for seizures has been reported.
In the presence of a positive history of seizures, patients should be advised to
inform their doctor.

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidases (MAOIs); at the
doses used for antibacterial therapy, however, it does not exert an antidepressant effect. Very limited data are available from drug interaction studies and on the safety of linezolid
administered to patients with pre-existing clinical conditions and/or undergoing concomitant pharmacological therapies that may put them at risk due to MAO inhibition. The use of
linezolid is therefore not recommended in these circumstances, unless close
surveillance and monitoring are possible.

Use with foods rich in tyramine
Patients should be advised not to consume large amounts of foods rich in tyramine.

Superinfections
Clinical studies have not evaluated the effects of linezolid therapy on the normal flora.
The use of antibiotics can sometimes cause an overgrowth of non-susceptible microorganisms. For
example, approximately 3% of patients treated with the recommended dose of linezolid experienced the onset
of drug-related candidiasis during clinical studies. If a superinfection occurs
during therapy, appropriate measures should be taken.

Special populations
Linezolid should be used with particular caution in patients with severe renal insufficiency and only
when the expected benefit is considered to outweigh the theoretical risks.
It is recommended to administer linezolid in patients with severe hepatic insufficiency only when the
expected benefit outweighs the theoretical risk.

Impairment of fertility
Linezolid has reversibly reduced fertility and induced morphological abnormalities of sperm in
adult male rats at exposure levels equivalent to those expected in humans; possible effects
of linezolid on the male reproductive system in humans are unknown.

Clinical studies
The safety and efficacy of linezolid administered for periods longer than 28 days have not been
established.
Controlled clinical studies did not include patients with diabetic foot lesions, pressure ulcers, or ischemic lesions, severe burns or gangrene. Therefore, experience with the use of
linezolid in the treatment of such lesions is limited.

Excipients
300 ml of solution contain 13.7 g of glucose. Patients with rare glucose-galactose malabsorption should not use this medicine.
300 ml of solution also contains 114 mg of sodium (5 mmol). The sodium content should be
taken into consideration in patients following a low-sodium diet.

Interactions

Monoamine Oxidase Inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidases (MAOIs). Very limited data are available from both drug interaction studies and on the safety of linezolid administered to patients undergoing concomitant therapy with medications that may entail a risk of MAO inhibition. The use of linezolid is therefore not recommended in these circumstances, unless close monitoring and accurate monitoring of the recipient are possible.

Potential interactions producing increases in blood pressure
In healthy volunteers with normal blood pressure, linezolid potentiated the increase in blood pressure induced by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine induced average increases in systolic blood pressure of approximately 30-40 mmHg, compared to increases of 11-15 mmHg with linezolid alone, 14-18 mmHg with pseudoephedrine or phenylpropanolamine alone, and 8-11 mmHg with placebo. Analogous studies have not been conducted in hypertensive subjects. It is recommended to carefully titrate the dosage of medications with vasopressor action, including dopaminergic substances, in order to achieve the desired response when administered concurrently with linezolid.

Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan has been studied in healthy volunteers. Subjects were treated with dextromethorphan (two 20 mg doses administered at an interval of 4 hours), with or without linezolid. In normal subjects treated with linezolid and dextromethorphan, no effect of the serotonergic syndrome (confusion, delirium, agitation, tremors, erythema, diaphoresis, hyperpyrexia) was observed.
Post-marketing experience: one report of a patient who manifested effects similar to those of the serotonergic syndrome during concomitant use of linezolid and dextromethorphan has been reported, which resolved with discontinuation of both treatments.
In clinical experience with the concomitant use of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), cases of serotonergic syndrome have been reported. Concomitant administration is therefore contraindicated, but the management of patients for whom treatment with linezolid and serotonergic agents is essential is described in the “Warnings and precautions” section.

Use with foods rich in tyramine
Subjects treated with linezolid and less than 100 mg of tyramine did not exhibit any significant pressor response. This indicates that it is only necessary to avoid ingesting excessive amounts of foods and beverages with a high tyramine content (e.g., aged cheese, yeast extracts, non-distilled alcoholic beverages and fermented soy products such as soy sauce).

Drugs metabolized by cytochrome P450
Linezolid is not metabolized to a detectable extent by the cytochrome P450 (CYP) enzyme system and does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-induced drug interaction with linezolid is expected.

Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid has been studied in sixteen healthy adult male volunteers who were administered linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin lowered the Cmax and AUC of linezolid by an average of 21% [90% CI, 15, 27] and 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin
When warfarin was associated with linezolid therapy, in steady-state conditions, a 10% reduction in the average maximum INR was observed during concomitant administration, with a 5% reduction in the AUC INR. The clinical significance of these findings, if any, cannot be defined, as the data of patients treated with warfarin and linezolid are insufficient.

Fertility, pregnancy and lactation
Pregnancy
Adequate data on the use of linezolid in pregnant women are not available. Studies conducted on animals have shown toxic effects on reproduction. A potential risk to humans exists.
Linezolid should not be used during pregnancy unless strictly necessary, i.e. only when the expected benefits outweigh the theoretical risk.
Lactation
Animal data indicate that linezolid and its metabolites can pass into breast milk and, consequently, breastfeeding should be discontinued before and during administration.
Fertility
In animal studies, linezolid has caused a reduction in fertility.

Effects on ability to drive and operate machinery
Patients should be informed about the potential occurrence of dizziness or impaired vision during treatment with linezolid, and should therefore be warned not to drive vehicles or operate machinery if any of these symptoms occur.

Undesirable effects
The following table lists the adverse drug reactions that have occurred with a frequency based on data for all causes from clinical studies in which over 2,000 adult patients were enrolled, who were treated for up to 28 days with the recommended doses of linezolid. Those reported most commonly were diarrhea (8.4%), headache (6.5%), nausea (6.3%) and vomiting (4.0%).

• Drug-related adverse events most commonly reported that caused discontinuation of treatment were headache, diarrhea, nausea and vomiting. Approximately 3% of patients discontinued treatment following the onset of a drug-related adverse event.
  Further adverse reactions reported during post-marketing experience are included in the “not known” category, as the actual frequency cannot be defined from the available data.
  The following undesirable effects have been observed and reported during treatment with linezolid at the following frequencies: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known (the frequency cannot be defined on the basis of the available data).

* See section “Warnings and special precautions for use”
** See sections “Contraindications” and “Interactions”
† See information below
The following adverse reactions to linezolid have been considered serious in rare cases: localized abdominal pain, transient ischemic attacks and hypertension.
†In clinical controlled studies in which linezolid was administered for up to 28 days of treatment, anemia was reported in 2% of patients. During a compassionate use program in patients with potentially fatal infections and concomitant underlying conditions, the percentage of patients who developed anemia during treatment with linezolid for ≤ 28 days was 2.5% (33/1,326), compared to 12.3% (53/430) in cases where therapy was > 28 days. The percentage of cases in which drug-related severe anemia requiring blood transfusion was reported 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 conducted on over 500 paediatric patients (from birth to 17 years) do not indicate that the safety profile of linezolid for paediatric patients differs from that of adults.

Overdosage
There is no specific antidote known.
No cases of overdosage have been reported. The following information may be useful, however:
Supportive treatment is recommended together with maintaining glomerular filtration.
Approximately 30% of a dose of linezolid is removed in 3 hours of hemodialysis, but no data are available on the removal of linezolid by peritoneal dialysis or hemoperfusion. The two main metabolites of linezolid are also removed to some extent by hemodialysis.

Instructions for use and handling
For single use only. Remove the outer packaging only when ready for use, then check for leaks by firmly compressing the bag. If there are leaks from the bag, do not use as sterility may be compromised. The solution must be visually inspected before use and only clear solutions, without particles, must be used. Do not use the bags in series connections. Unused solution must be discarded. No special requirements for disposal.
Any unused medicine or waste derived from such medicine must be disposed of in accordance with local regulations. 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 solution, Ringer’s lactate solution for injectable preparations (Hartmann’s solution for injection).

Incompatibilities
Additives must not be introduced into this solution. If linezolid must be
administered in association with other drugs, each drug must be administered
separately according to the instructions for use. Similarly, if the same intravenous line must be
used for the sequential infusion of different drugs, the line must be flushed before and after the
administration of linezolid 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 sulfamethoxazole / trimethoprim. Furthermore, it is chemically incompatible with ceftriaxone
sodium.

Shelf life
2 years.

After first opening:chemical and physical stability has been demonstrated for 24 hours at room temperature
in the primary packaging, bag, after removal of the secondary packaging (overbag). From a
microbiological point of view, the product must be used immediately. If not used
immediately, the times and conditions prior to use are the responsibility of the user.

Special precautions for storage
Do not store at temperatures above 30° C.
Store in the original packaging to protect the medicine from light.