Linezolid krka

Package leaflet: Information for the user

Linezolid Krka, 2 mg/ml, infusion solution
Linezolidum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, including any adverse reactions not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

1. What Linezolid Krka is and what it is used for
2. Important information before using Linezolid Krka
3. How to use Linezolid Krka
4. Possible side effects
5. How to store Linezolid Krka
6. Contents of the pack and other information

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

Linezolid Krka is an antibiotic belonging to the class of antibiotics known as oxazolidinones, which works by inhibiting the growth of certain bacteria causing infections in adults.
This medicine is used to treat pneumonia and certain skin and soft tissue infections. Your doctor will decide whether Linezolid Krka is appropriate for treating your specific infection.

2. Important information before using Linezolid Krka

When not to use Linezolid Krka

• if the patient is allergic to linezolid or to any of the other ingredients of this medicine (listed in section 6);
• if the patient is currently taking or has taken within the last 2 weeks medicines from a group called monoamine oxidase inhibitors (MAOIs), e.g. phenelzine, isocarboxazid, selegiline, moclobemide. These medicines may be used in the treatment of depression or Parkinson's disease;
• during breastfeeding, because linezolid passes into breast milk and may harm the baby.

Warnings and precautions
Before starting treatment with Linezolid Krka, discuss this with your doctor, pharmacist or nurse.
Linezolid Krka may not be suitable for the patient if he or she can answer "yes" to any of the following questions. In such cases, talk to your doctor, as it will be necessary to check the patient's general health and blood pressure before and during treatment. The doctor may also decide to prescribe another medicine.
If in doubt whether any of the situations below apply to the patient, consult your doctor.

• Does the patient have high blood pressure and is taking medicines for it or not?
• Has the patient been diagnosed with hyperthyroidism?
• Does the patient have a tumour of the adrenal gland (pheochromocytoma) or carcinoid syndrome (caused by tumours in the hormonal system, associated with symptoms such as diarrhoea, skin flushing, wheezing)?
• Does the patient have bipolar affective disorder, schizoaffective disorders, disorientation or other psychiatric disorders?
• Has the patient experienced hyponatraemia (low sodium levels in the blood) or is taking medicines that reduce sodium levels in the blood, e.g. certain diuretics (also called "water tablets"), such as hydrochlorothiazide?
• Is the patient taking any opioid medicines? Concurrent use of certain medicines, including antidepressants and opioids, with Linezolid Krka may lead to serotonin syndrome – a potentially life-threatening condition (see section 2 "Linezolid Krka and other medicines" and section 4).

When to exercise caution when using Linezolid Krka
Inform the doctor before taking Linezolid Krka if the patient has:

• advanced age,
• tendency to bruise or bleed easily,
• anaemia (low number of red blood cells),
• tendency to infections,
• history of seizures,
• liver or kidney function disorders, especially if the patient is on dialysis,
• diarrhoea.

Tell the doctor immediately if the patient experiences any of the following during treatment:

• vision problems, e.g. blurred vision, changes in colour vision, difficulty seeing details or narrowing of the visual field;
• loss of sensation in the hands or feet or tingling or prickling sensations in the hands and feet;
• diarrhoea may occur during or after taking antibiotics, including Linezolid Krka. If severe, persistent diarrhoea develops, or if blood or mucus appears in the stool, stop taking Linezolid Krka immediately and contact your doctor. In such cases, do not take medicines that stop or slow down intestinal movements;
• recurring nausea or vomiting, abdominal pain or rapid breathing;
• unexplained muscle pain, tenderness or weakness and (or) dark discoloration of urine. These may be symptoms of a serious condition called rhabdomyolysis (muscle breakdown), which may lead to kidney damage;
• nausea and feeling unwell, including muscle weakness, headache, confusion and memory disturbances, which may indicate hyponatraemia (low sodium levels in the blood).

Linezolid Krka and other medicines
There is a risk of interactions between Linezolid Krka and other medicines. These interactions may lead to adverse effects, such as changes in blood pressure, body temperature or heart rate.
Tell your doctor about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
Inform your doctor if you are currently taking or have taken any of the following medicines within the last 2 weeks, because Linezolid Krka must not be used during treatment with or shortly after treatment with these medicines (see also section 2 above: "When not to use Linezolid Krka"):

• monoamine oxidase inhibitors (MAOIs: e.g. phenelzine, isocarboxazid, selegiline, moclobemide); these medicines may be used in the treatment of depression or Parkinson's disease.

Also inform your doctor if the patient is taking any of the following medicines. The doctor may still prescribe Linezolid Krka, but monitoring of the patient's general health and blood pressure before and during treatment will be necessary. In other cases, the doctor may decide that another medicine would be more suitable for the patient.

• Decongestants used for cold or flu containing pseudoephedrine or phenylpropanolamine.
• Certain anti-asthma medicines, e.g. salbutamol, terbutaline, fenoterol.
• Tricyclic antidepressants or SSRIs (selective serotonin reuptake inhibitors). Many medicines belong to these groups, e.g. amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• Anti-migraine medicines, e.g. sumatriptan and zolmitriptan.
• Medicines used to treat sudden, severe allergic reactions, e.g. adrenaline (epinephrine).
• Medicines that increase blood pressure, e.g. noradrenaline (norepinephrine), dopamine and dobutamine.
• Opioids, e.g. pethidine – used to treat moderate to severe pain.
• Medicines used to treat anxiety disorders, e.g. buspirone.
• Anticoagulants, e.g. warfarin.
• An antibiotic called rifampicin.

Linezolid Krka with food and drink

• Linezolid Krka may be taken regardless of meals.
• During treatment, avoid foods such as mature cheeses, yeast extracts, soy products (e.g. soy sauce) and alcoholic beverages, especially draught beer and wine. These products contain tyramine, which may interact with Linezolid Krka and cause an increase in blood pressure.
• If a pulsating headache occurs after eating or drinking, consult your doctor, pharmacist or nurse immediately.

Pregnancy, breastfeeding and fertility
The effects of linezolid in pregnant women are unknown. Therefore, unless otherwise advised by a doctor, Linezolid Krka should not be used during pregnancy. If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to become pregnant, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding must be discontinued during treatment with Linezolid Krka, because this medicine passes into breast milk and may harm the baby.

Driving and operating machinery
Linezolid Krka may cause dizziness or visual disturbances. In such cases, do not drive or operate machinery. Remember that feeling unwell may adversely affect the ability to drive and operate machinery.

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

Linezolid Krka contains sodium
300 ml of infusion solution contains 114 mg of sodium (the main component of table salt). This corresponds to 5.7% of the maximum recommended daily intake of sodium in the adult diet.

3. How to use Linezolid Krka

Adults
This medicine should always be used exactly as described in this patient information leaflet or as directed by your doctor, pharmacist, or nurse. If in doubt, consult your doctor, pharmacist, or nurse.
Linezolid Krka will be administered as an intravenous infusion (drip into a vein) by a doctor or healthcare professional. The usual dose for adult patients (aged 18 years and older) is 300 ml of solution (600 mg of linezolid) given twice daily directly into the bloodstream (intravenously) via infusion over 30 to 120 minutes.
If undergoing dialysis, Linezolid Krka should be administered after the dialysis session.
Treatment typically lasts from 10 to 14 days, but may extend up to 28 days. The efficacy and safety of treatment periods longer than 28 days have not been established. The required duration of treatment will be determined by the doctor.
While receiving Linezolid Krka, your doctor will recommend regular blood tests to monitor blood counts.
If Linezolid Krka is used for longer than 28 days, an eye examination should be performed.

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

Taking more Linezolid Krka than recommended
If you feel that you have received too high a dose, contact your doctor or nurse immediately.

Missing a dose of Linezolid Krka
Since this medicine will be administered under strict medical supervision, missing a dose is unlikely. However, if a dose is suspected to have been missed, inform your doctor or nurse immediately. Do not use a double dose to make up for a missed dose.

If you have any further questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
If any of the following adverse reactions occur in a patient treated with Linezolid Krka, you should immediately inform the doctor, nurse or
pharmacist:

Serious adverse reactions associated with the use of Linezolid Krka (with frequency stated in parentheses) are as follows:

• severe skin reactions (uncommon), swelling especially in the face and neck area (uncommon), wheezing and (or) difficulty breathing (rare). These may be symptoms of an allergic reaction and may require discontinuation of Linezolid Krka. Skin reactions such as: raised, purple rash caused by inflammation of blood vessels (vasculitis) (rare); redness, peeling of the skin (skin inflammation) (uncommon), rash (common), itching (common).
• visual disturbances (uncommon), such as blurred vision (uncommon), changes in colour perception (frequency not known), difficulty in seeing details (frequency not known), or narrowing of the visual field (rare).
• severe diarrhoea with blood and (or) mucus in the stool (antibiotic-associated colitis, including pseudomembranous colitis), rarely leading to life-threatening complications (uncommon).
• recurrent nausea or vomiting, abdominal pain or rapid breathing (rare).
• seizures or convulsions have been reported (uncommon) during treatment with Linezolid Krka.
• serotonin syndrome (frequency not known): Inform your doctor if, when taking antidepressants of the SSRI group or opioids simultaneously, symptoms such as excessive agitation, confusion, disorientation, rigidity, tremor, lack of coordination, convulsive seizures, rapid heartbeat, severe breathing problems and diarrhoea occur (suggesting serotonin syndrome) (see section 2).
• bleeding or bruising of unknown cause, possibly due to changes in blood cell counts affecting blood clotting processes or leading to anaemia (common).
• changes in the number of certain blood cells, which may affect the ability to fight infections (uncommon); signs of infection include: fever (common), sore throat (uncommon), mouth ulcers (uncommon), fatigue (uncommon).
• rhabdomyolysis (rare): objective and subjective symptoms include unexplained muscle pain, tenderness or weakness and (or) dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which may lead to kidney damage.
• pancreatitis (uncommon).
• convulsions (uncommon).
• transient ischaemic attacks (transient disturbances in blood supply to the brain causing temporary symptoms such as loss of vision, limb weakness, slurred speech, loss of consciousness) (uncommon).
• "ringing" in the ears (tinnitus) (uncommon).

In patients treated with Linezolid Krka for more than 28 days, numbness, tingling or blurred vision have been reported. If visual disturbances occur, contact a doctor immediately.

Additional adverse reactions include:

Common adverse reactions (may occur in less than 1 in 10 people):

• fungal infections, particularly vaginal or oral thrush
• headache
• metallic taste in the mouth
• diarrhoea, nausea or vomiting
• changes in certain blood test results, including those measuring proteins, salts or enzymes used to assess kidney or liver function, or blood glucose levels
• sleep disturbances
• increased blood pressure
• anaemia (low number of red blood cells)
• dizziness
• localised or generalised abdominal pain
• constipation
• digestive disorders (dyspepsia)
• local pain
• decreased platelet count

Uncommon adverse reactions (may occur in less than 1 in 100 people):

• inflammation of the vaginal mucosa or genital area in women
• sensation of numbness or tingling
• swelling, pain or discolouration of the tongue
• dryness of the mouth
• pain at or around the site of infusion (drip)
• vein inflammation (including at the infusion site)
• frequent urination
• chills
• increased thirst
• increased sweating
• hyponatraemia (low sodium levels in the blood)
• kidney dysfunction
• bloating
• injection site pain
• increased creatinine levels
• abdominal pain
• changes in heart rate frequency (e.g. increased rate)
• decreased number of all types of blood cells
• weakness and (or) sensory changes

Rare adverse reactions (may occur in less than 1 in 1000 people):

• superficial tooth discoloration, reversible after dental cleaning (manual removal of tartar)

The following adverse reactions have also been reported (frequency not known: frequency cannot be determined from available data):

• hair loss (alopecia)

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Linezolid Krka

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging following the abbreviation
"EXP". The expiry date refers to the last day of the stated month.
Do not store above 30 °C.
Store in the original packaging to protect from light.
After opening: chemical and physical stability of the solution in an infusion bag has been demonstrated for
24 hours at room temperature after removal from the outer bag.
From a microbiological point of view, the medicine should be used immediately. If the medicine is not used immediately, the user is solely responsible for the storage conditions and duration.
Do not use the medicine if the solution is not clear, colourless to yellow or yellowish-brown.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such 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 infusion solution contains 2 mg of linezolid. A 300 ml infusion bag contains 600 mg of linezolid.
• Other components are monohydrate glucose, disodium citrate dihydrate, citric acid, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), and water for injections. See section 2, "Linezolid Krka contains glucose" and "Linezolid Krka contains sodium".

What Linezolid Krka looks like and contents of the pack
A clear, colourless to yellow or yellowish-brown solution (pH: 4.6–5.2; osmolality:
270 mOsmol/kg – 320 mOsmol/kg).
Immediate packaging:
Infusion bag (300 ml) made of multilayer polyolefin film, with a port of multilayer
polyolefin coating and a polyolefin twist-off connector.
Outer packaging:
Multilayer outer bag made of Polyester/Aluminum/Polyester/Polypropylene film, in a cardboard box. Outer bags are packed in cardboard boxes containing 1 or 10 bags.
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 medicinal product is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

For more detailed information about this medicinal product, please contact the local representative of the marketing authorization holder:
KRKA-POLSKA Sp. z o.o.
Równoległa 5
02-235 Warsaw
Tel. 22 57 37 500

Information intended exclusively for healthcare professionals:

Linezolid Krka, 2 mg/ml, infusion solution
Linezolidum
IMPORTANT: Before prescribing this medicinal product, please read the Summary of Product Characteristics.
Linezolid is ineffective in the treatment of infections caused by Gram-negative bacteria.
Specific treatment against Gram-negative microorganisms should therefore be initiated simultaneously in cases of confirmed or suspected presence of Gram-negative bacteria.

Description
The packaging is intended for single use only. The bag contains 300 ml of infusion solution and is placed in a cardboard box. Each box contains either 1 or 10 infusion bags.
Linezolid Krka contains 2 mg of linezolid per 1 ml of infusion solution. The solution is clear, colourless to yellow or yellowish-brown. The excipients are: glucose monohydrate, disodium citrate dihydrate, citric acid, hydrochloric acid, sodium hydroxide, and water for injections.

Dosage and administration
Treatment with linezolid should be initiated only in hospital settings and after consultation with a specialist, e.g. a microbiologist or an infectious disease specialist.
Patients who begin treatment with the intravenous formulation may be switched to the oral formulation when clinically appropriate. In such cases, dosage adjustment is not required, as the oral bioavailability of linezolid is approximately 100%.
The infusion solution should be administered by intravenous infusion over a period of 30 to 120 minutes.
The recommended dose of linezolid is given intravenously twice daily.

Recommended dose and duration of treatment in adults
The duration of treatment depends on the type of pathogenic microorganism, site and severity of infection, and the patient's clinical response to therapy.
The treatment duration recommendations presented below are consistent with those used in clinical trials. In certain types of infections, a shorter duration of linezolid treatment may be sufficient; however, clinical trial data on such shorter regimens are lacking.
The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been established.
Dosage recommendations for intravenous infusion solution and tablets or granules for oral suspension are identical and are as follows:

Children and adolescents: The safety and efficacy of linezolid in children and adolescents (aged <18 years) have not been established. Currently available data are presented in the SmPC in sections 4.8, 5.1 and 5.2, but dosing recommendations cannot be determined.

Elderly patients: No dose adjustment is necessary.

Renal impairment: No dose adjustment is required.

Severe renal impairment (i.e. creatinine clearance <30 ml/min): No dose adjustment is required. Due to the uncertain clinical significance of increased exposure (up to 10-fold) to two major metabolites of linezolid in patients with severe renal failure, linezolid should be used with particular caution and only when the anticipated benefit outweighs the potential risk. Since approximately 30% of a dose of linezolid is removed during a 3-hour haemodialysis session, Linezolid Krka should be administered after haemodialysis. Haemodialysis also partially removes the primary metabolites of linezolid, but their concentrations remain substantially higher after dialysis than those observed in patients with normal or mild to moderate renal function. Therefore, in patients with severe renal impairment undergoing dialysis, linezolid should be used with particular caution and only when the anticipated benefit outweighs the potential risk.

Currently, there are no data on the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or other forms of renal replacement therapy besides haemodialysis.

Hepatic impairment: Patients with mild to moderate hepatic impairment (Child-Pugh class A or B): No dose adjustment is necessary.

Severe hepatic impairment (Child-Pugh class C): Since linezolid is metabolised via non-enzymatic pathways, it is expected that hepatic impairment does not significantly affect its metabolism; therefore, no dose adjustment is required. However, clinical data are limited. Linezolid should be used with caution in these patients and only when the anticipated benefit outweighs the potential risk.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Linezolid must not be administered concomitantly with monoamine oxidase inhibitors of type A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of discontinuation of such agents.

Linezolid must not be given to patients with any of the following underlying conditions or receiving any of the following medications unless close monitoring of the patient and blood pressure surveillance are ensured:

• Patients with untreated hypertension, phaeochromocytoma, carcinoid tumour, hyperthyroidism, bipolar affective disorders, schizoaffective disorders, acute confusional states.
• Patients receiving any of the following medications: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin receptor agonists (triptans), medicinal products with direct or indirect sympathomimetic activity (including bronchodilators, pseudoephedrine and phenylpropanolamine), vasoconstrictive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), meperidine or buspirone.

Breast-feeding must be discontinued prior to and during treatment with linezolid.

Special warnings and precautions for use

Bone marrow suppression

Thrombocytopenia, anaemia, leukopenia and pancytopenia have been reported in patients treated with linezolid. In cases where these effects were identified, blood parameters returned to pre-treatment values after discontinuation of linezolid. The occurrence of such events appears to be related to the duration of treatment. Elderly patients treated with linezolid are at greater risk of blood count abnormalities than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal impairment, regardless of whether they are undergoing dialysis. Therefore, blood counts should be closely monitored in patients with pre-existing anaemia, granulocytopenia or thrombocytopenia, in patients receiving concomitant medications that may reduce haemoglobin levels, blood cell counts or affect platelet number or function, in patients with severe renal impairment, and in patients receiving linezolid for longer than 10 to 14 days. Linezolid may be administered to these patients only if close monitoring of haemoglobin, blood cell counts and platelet counts is possible. If significant bone marrow suppression occurs during treatment with linezolid, the medicinal product should be discontinued unless its continued use is absolutely necessary. In such cases, blood parameters should be monitored closely and appropriate management initiated.

Furthermore, weekly monitoring of a complete blood count (including haemoglobin, platelet count and white blood cell count with differential) is recommended in all patients receiving linezolid, regardless of initial blood count results.

In compassionate use studies involving administration of linezolid prior to marketing authorisation, an increased incidence of severe anaemia was observed in patients who received linezolid for longer than the maximum recommended duration of 28 days. Blood transfusions were more frequently required in these patients. Cases of anaemia requiring blood transfusion have also been reported post-marketing, more frequently after treatment exceeding 28 days.

Post-marketing cases of sideroblastic anaemia have been reported. Most patients who developed initial symptoms had received linezolid for longer than 28 days. After discontinuation of linezolid, anaemia resolved completely or partially in most patients, whether or not treated.

Increased mortality in a clinical trial in patients with Gram-positive bacteraemia associated with intravascular catheters

In an open-label clinical trial in critically ill patients with catheter-related infections, higher mortality was observed in patients receiving linezolid compared to those treated with vancomycin, dicloxacillin or oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing mortality was the presence of Gram-positive bacterial infection at baseline. Mortality rates were similar in patients with infection caused exclusively by Gram-positive bacteria (odds ratio 0.96; 95% CI: 0.58–1.59), but were significantly higher (p=0.0162) in the linezolid group among patients with any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% CI: 1.38–4.46). The greatest difference occurred during treatment and within 7 days after its completion. During the study, more patients in the linezolid group became colonised with Gram-negative pathogens and died from Gram-negative or mixed infections. Therefore, in complicated skin and soft tissue infections, linezolid may be used in patients with confirmed or suspected concomitant Gram-negative infection only when no alternative treatment options are available. In such cases, concomitant anti-Gram-negative therapy should be initiated promptly.

Diarrhoea and antibiotic-associated colitis

Pseudomembranous colitis and Clostridium difficile-associated diarrhoea have been reported during treatment with nearly every antibacterial agent, including linezolid. This complication may range from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhoea after administration of linezolid. If antibiotic-associated diarrhoea or colitis is suspected and/or confirmed, discontinuation of the antibacterial agent, including linezolid, is recommended, and appropriate treatment should be initiated promptly. In such cases, the use of drugs that inhibit intestinal motility is contraindicated.

Lactic acidosis

Lactic acidosis has been reported during treatment with linezolid. In patients who develop clinical and laboratory signs of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation, immediate medical intervention is required. If lactic acidosis occurs, the benefit-risk ratio of continuing linezolid therapy should be evaluated before resuming treatment.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis, which may lead to adverse effects such as lactic acidosis, anaemia and neuropathy (optic or peripheral). These symptoms occur more frequently when linezolid is administered for longer than 28 days.

Serotonin syndrome

Cases of serotonin syndrome associated with concomitant administration of linezolid and serotonergic drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, have been reported in spontaneous reports (see SmPC section 4.5). Therefore, concomitant administration of linezolid with serotonergic medicinal products is contraindicated (see Sm游戏副本, section 4.3), except when absolutely necessary.

In such cases, patients should be closely monitored for clinical and laboratory signs of serotonin syndrome, such as cognitive disturbances, hyperthermia, hyperreflexia and lack of coordination. If such symptoms occur, the physician should consider discontinuing one or both drugs. Symptoms of withdrawal may occur after discontinuation of serotonergic drugs.

Rhabdomyolysis

Cases of rhabdomyolysis associated with linezolid have been reported. Linezolid should be used with caution in patients with predisposing factors for rhabdomyolysis. If clinical or laboratory signs of rhabdomyolysis occur, linezolid should be discontinued and appropriate treatment initiated.

Hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Cases of hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients treated with linezolid. In patients at risk of hyponatraemia, such as elderly patients or those receiving drugs that may reduce serum sodium levels (e.g. thiazide diuretics such as hydrochlorothiazide), regular monitoring of serum sodium concentration is recommended.

Peripheral neuropathy and optic neuropathy

Cases of peripheral neuropathy and optic neuropathy, sometimes leading to vision loss, have been reported in patients treated with linezolid; these reports primarily involved patients treated for longer than the maximum recommended duration of 28 days.

Patients should be advised to report symptoms of visual deterioration such as changes in visual acuity, colour vision changes, blurred vision or visual field defects. In such cases, prompt ophthalmological evaluation is recommended. In patients receiving linezolid for longer than the maximum recommended 28 days, regular monitoring of visual function should be performed.

If peripheral or optic neuropathy occurs, the benefit-risk ratio of continuing linezolid therapy should be evaluated.

Increased risk of neuropathy may occur when linezolid is administered to patients currently or recently receiving anti-tuberculosis medicinal products.

Seizures

Seizures have been reported in patients treated with linezolid. In most of these cases, a history of seizures or risk factors for seizures was present. Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). However, at doses used for the treatment of infections, it does not produce antidepressant effects. Data from drug interaction studies and the risk of using linezolid in patients with other diseases and/or concomitant medicinal products that may pose a risk related to MAO inhibition are limited. Linezolid should not be used unless close monitoring and supervision of the patient are possible.

Consumption of tyramine-rich foods

Patients should be instructed to limit the consumption of foods rich in tyramine during treatment with linezolid.

Superinfections

The effect of linezolid on normal bacterial flora has not been evaluated in clinical trials.

Antibiotic use may occasionally lead to overgrowth of resistant microorganisms. For example, during clinical trials, approximately 3% of patients receiving recommended doses of linezolid developed drug-induced candidiasis. If superinfection with resistant microorganisms occurs during linezolid therapy, appropriate treatment should be initiated.

Special patient groups

Linezolid should be used with particular caution in patients with severe renal impairment and only when the anticipated benefit outweighs the theoretical risk (see SmPC sections 4.2 and 5.2).

Linezolid should be used in patients with severe hepatic impairment only when the anticipated benefit outweighs the risk.

Fertility

Administration of linezolid resulted in reversible reduction in fertility and induced abnormalities in sperm morphology in adult male rats exposed to linezolid at levels similar to those in humans. There are no data on the effects of linezolid on the male reproductive system in humans.

Clinical trials

The safety and efficacy of linezolid administered for longer than 28 days have not been established. Controlled clinical trials have not been conducted in patients with diabetic foot, pressure ulcers, ischaemic lesions, severe burns or gangrene. Experience with the use of linezolid in such cases is limited.

Excipients

300 ml of solution contains 13.7 g of glucose. This should be taken into account in diabetic patients.

300 ml of solution also contains 114 mg (5 mmol) of sodium, which corresponds to 5.7% of the WHO-recommended maximum daily intake of 2 g of sodium for adults.

Interactions

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Data from drug interaction studies and the risk of using linezolid in patients receiving concomitant medicinal products that may inhibit monoamine oxidase (MAO) are limited. Linezolid should not be used unless close monitoring and supervision of the patient are possible.

Potential interactions leading to increased blood pressure

In healthy volunteers, linezolid has been shown to potentiate the blood pressure-increasing effect of pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid and pseudoephedrine or phenylpropanolamine resulted in an increase in systolic blood pressure of 30–40 mmHg, compared to an increase of 11–15 mmHg with linezolid alone, 14–18 mmHg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mmHg with placebo. Similar studies have not been conducted in patients with hypertension. Gradual dose adjustment of vasoactive drugs (including dopaminergic receptor agonists) is recommended when administered concomitantly with linezolid.

Potential interactions with serotonergic drugs

Interactions between linezolid and dextromethorphan were studied in healthy volunteers. Dextromethorphan (two 20 mg doses administered 4 hours apart) was given with or without linezolid. No symptoms of serotonin syndrome (e.g. disorientation, delirium, restlessness, tremor, facial flushing, profuse sweating, hyperthermia) were observed in patients receiving both linezolid and dextromethorphan.

Post-marketing, one case of symptoms suggestive of serotonin syndrome was reported following concomitant administration of linezolid and dextromethorphan. Symptoms resolved after discontinuation of both medicinal products.

During clinical trials, cases of serotonin syndrome were reported during concomitant use of linezolid and serotonergic medicinal products, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, their concomitant use is not recommended (see SmPC section 4.3). Management of patients requiring concomitant administration of linezolid and serotonergic medicinal products is described in the special warnings and precautions for use.

Concomitant use with tyramine-rich foods

No significant increase in blood pressure was observed in patients receiving linezolid together with tyramine doses below 100 mg. This indicates that only excessive consumption of foods and beverages high in tyramine (e.g. aged cheeses, yeast extracts, non-distilled alcoholic beverages and fermented soy products such as soy sauce) should be avoided.

Medicinal products metabolised by cytochrome P450

Linezolid is not significantly metabolised by the cytochrome P450 (CYP450) enzyme system and does not inhibit the activity of any human CYP isoenzymes of clinical significance (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, drug interactions related to CYP450 activity are not expected during linezolid therapy.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was evaluated in 16 healthy male subjects who received 600 mg linezolid twice daily for 2.5 days or linezolid with 600 mg rifampicin once daily for 8 days. Rifampicin reduced Cmax and AUC of linezolid by a mean 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 is added during linezolid treatment after steady-state concentrations are achieved, a 10% decrease in mean maximum INR (International Normalised Ratio) values and a 5% decrease in AUC for INR are observed. There are insufficient data to determine the clinical significance of concomitant use of linezolid and warfarin.

Effects on fertility, pregnancy and lactation

Pregnancy

Data on the use of linezolid in pregnant women are limited. Animal studies have shown toxic effects of linezolid on reproduction. There is a potential risk when used in humans.

Linezolid should not be used during pregnancy unless, in the opinion of the physician, the benefits outweigh the potential risks.

Lactation

Animal studies indicate that linezolid and its metabolites may pass into breast milk of nursing mothers; therefore, breast-feeding must be discontinued prior to and during treatment with linezolid.

Fertility

In animal studies, linezolid caused reduced fertility.

Effects on ability to drive and use machines

Patients should be warned that dizziness and visual disturbances may occur during treatment with linezolid and that they should not drive or operate machinery if affected.

Adverse reactions

The adverse events listed in the table below occurred at frequencies observed in clinical trials involving over 6,000 adult patients who received linezolid at recommended doses for up to 28 days.

The most commonly reported adverse events were: diarrhoea (8.9%), nausea (6.9%) and vomiting (4.3%), and headache (4.2%).

The most commonly reported adverse events associated with linezolid use that led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. Approximately 3% of patients discontinued treatment due to an adverse event related to linezolid use.

Additional adverse reactions reported post-marketing are listed below and described as "frequency not known" because the actual frequency cannot be determined from available data.

The following adverse reactions have been observed during treatment with linezolid, with the following frequency categories:

• 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),
• frequency not known (frequency cannot be estimated from the available data).

The following adverse reactions of linezolid were rarely severe: localized abdominal pain, transient ischaemic attacks and hypertension.
†In controlled clinical trials in which linezolid was administered for up to 28 days, anaemia occurred in 2% of patients. In trials involving the use of linezolid in exceptional cases prior to marketing approval (compassionate use) in patients with life-threatening infections and co-morbid conditions, anaemia developed in 2.5% (33/1326) of patients treated with linezolid for up to 28 days and in 12.3% (53/430) of patients treated for longer than 28 days. Severe anaemia associated with linezolid use requiring blood transfusion occurred in 9% (3/33) of patients treated for up to 28 days and in 15% (8/53) of patients treated for longer than 28 days.

Children and adolescents
Safety data obtained from clinical trials involving over 500 patients aged from birth to 17 years do not indicate that the safety profile of linezolid in the paediatric and adolescent population differs from that observed in adult patients.

Overdose
There is no specific antidote.
No cases of linezolid overdose have been reported. Nevertheless, the following information may be useful in managing overdose:
Supportive treatment to maintain vital functions and glomerular filtration should be administered. Approximately 30% of a dose of linezolid is removed during a 3-hour haemodialysis session; however, there are no data available on the removal of linezolid by peritoneal dialysis or haemoperfusion.

Special precautions for disposal and preparation of the medicinal product for administration
For single use only. Remove the outer bag immediately before administration and check for minor leaks by firmly squeezing the bag. If the bag leaks, do not use the product, as it may not be sterile. The solution should be inspected visually prior to administration and administered only if it is clear and free of particulate matter. Do not use in-line connectors. Any unused portion of the solution should be discarded. There are no special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local regulations. Do not connect bags with partially used contents.

Linezolid Krka infusion solution is compatible with the following solutions: 5% glucose infusion solution, 0.9% sodium chloride infusion solution, Ringer's lactate injection solution (Hartmann's solution).

Pharmaceutical incompatibilities
Do not add other substances to the solution. If linezolid is to be administered simultaneously with other medicinal products, each should be given separately, in accordance with the recommendations for their use. If linezolid solution and other medicinal products are to be administered alternately through the same intravenous access, they should be flushed with a solution compatible with linezolid infusion solution both before and after administration of linezolid.

Linezolid Krka infusion solution is physically incompatible with the following medicinal products: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin and sulfamethoxazole with trimethoprim. In addition, it is chemically incompatible with sodium ceftriaxone.

Shelf life
2 years

After opening: chemical and physical stability of the solution in the infusion bag has been demonstrated for 24 hours at room temperature after removal from the outer packaging (outer bag). From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the responsibility for the storage conditions and duration of use lies solely with the user.

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