Linezolid Krka

Package leaflet: Information for the user

Linezolid Krka 2 mg/ml infusion solution

Linezolid
Generic medicine
Please read this leaflet carefully before taking this medicine because 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 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 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 oxazolidinone group. It works by inhibiting the growth of certain bacteria that cause infections in adults. It is used to treat pneumonia and certain skin or soft tissue infections. Your doctor will decide whether Linezolid Krka is suitable for treating your infection.

2. What you need to know before taking Linezolid Krka

Do not take Linezolid Krka

• if you are allergic to linezolid or to 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, e.g. phenelzine, isocarboxazid, selegiline, moclobemide). These medicines may be used to treat depression or Parkinson’s disease.
• if you are breastfeeding, as Linezolid Krka passes into breast milk and may affect 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 you answer yes to any of the following questions.
In such cases, discuss with your doctor, as you may need to have your general health condition and blood pressure checked before and during treatment, or your doctor may decide that another treatment is more appropriate for you.
Ask your doctor if you are unsure whether any of these conditions apply to you.

• Do you have high blood pressure, even if you are taking medication for it?
• Have you been diagnosed with an overactive thyroid?
• Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumours of the hormonal system, with symptoms such as diarrhoea, 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 cold or flu 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 amitriptiline, 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 noradrenaline (norepinephrine), dopamine, and dobutamine
• medicines used to treat moderate to severe pain, such as meperidine
• medicines used to treat anxiety disorders, such as buspirone
• an antibiotic called rifampicin

Take special care with Linezolid Krka
Talk to your doctor before taking this medicine if:

• you bleed or bruise easily
• you are anaemic (have a low number of red blood cells)
• you tend to develop infections
• you have a history of seizures
• you have liver or kidney problems, especially if you are on dialysis
• you have diarrhoea

Contact your doctor immediately if, during treatment, you experience:

• vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or narrowing of your field of vision.
• loss of sensation in arms or legs or a tingling or prickling sensation in arms or legs.
• you may develop diarrhoea during or after taking antibiotics, including Linezolid Krka. If this becomes severe or persistent, or if you notice blood or mucus in your stools, stop taking Linezolid Krka immediately and consult your doctor. In this case, do not take medicines that block or slow down intestinal movement.
• recurrent 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 unwanted effects such as changes in blood pressure, body temperature, or heart rate.
Tell your doctor if you are taking or have taken any of the following medicines within the last 2 weeks, as Linezolid Krka must not be taken if you are currently taking or have recently taken these medicines. (See also section 2 above “Do not take Linezolid Krka”).

• Monoamine oxidase inhibitors (MAOIs, e.g. phenelzine, isocarboxazid, selegiline, moclobemide). These medicines may be used to treat depression or Parkinson’s disease.

Also inform your doctor if you are taking any of the following medicines. Your doctor may still decide to prescribe Linezolid Krka, but will need to monitor your general health and blood pressure before and during treatment. In other cases, your doctor may decide that another treatment is more suitable for you.

• Decongestant remedies for cold or flu containing pseudoephedrine or phenylpropanolamine.
• Certain 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 amitriptiline, 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 noradrenaline (norepinephrine), dopamine, and dobutamine.
• Medicines used to treat moderate to severe pain, such as meperidine.
• Medicines used to treat anxiety disorders, such as buspirone.
• Medicines that prevent blood clotting, such as warfarin. Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine.

Linezolid Krka with food and drink

• You may take Linezolid Krka before, during, or after a meal.
• Avoid eating large amounts of mature cheese, yeast extracts, or soya bean extracts (such as soy sauce), and avoid drinking alcohol, especially draught beer and wine. Linezolid Krka may react with a substance called tyramine, naturally present in some foods, causing an increase in blood pressure.
• If you develop a sudden, severe headache after eating or drinking, contact your doctor or pharmacist immediately.

Pregnancy, breastfeeding and fertility
The effects of Linezolid Krka in pregnant women are unknown. Therefore, it should not be taken during pregnancy unless advised by your doctor. If you are pregnant, think you may be pregnant, or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
You must not breastfeed while taking Linezolid Krka, as the medicine may pass into breast milk and could affect your baby.
Driving and using machines
Linezolid Krka may cause dizziness or vision problems. If this occurs, do not drive or operate machinery. Remember that your ability to drive or use machines may be impaired if you do not feel well.
Linezolid Krka contains glucose
300 ml of infusion solution contain 13.7 g of glucose. This should be taken into account in patients with diabetes mellitus.
Linezolid Krka contains sodium
300 ml of infusion solution contain 114 mg of sodium (5 mmol). This should be taken into account in patients on a sodium-controlled diet.

3. How to take Linezolid Krka

Adults
This medicine will be administered to you via an intravenous infusion by a doctor or healthcare professional.
The usual dose for adults (18 years and older) is 300 ml (600 mg of linezolid) given twice daily, administered directly into the bloodstream (intravenously) by infusion over a period of 30 to 120 minutes.
If you are undergoing renal dialysis, you should receive Linezolid Krka after the dialysis session.
A treatment course 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 exceeding 28 days. Your doctor will decide how long your treatment should last.
During treatment with Linezolid Krka, your doctor will perform regular blood tests to monitor your blood cell counts.
If you are treated with Linezolid Krka for more than 28 days, your doctor will monitor your vision.

Use in children and adolescents
Linezolid Krka is normally 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 this medicine is administered under close medical supervision, it is highly unlikely that a dose will be missed. If you think a dose has been missed, inform your doctor or nurse immediately.

If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Immediately inform your doctor, nurse or pharmacist if you notice any of the following side effects during treatment with Linezolid Krka:

• skin reactions such as red, painful skin and peeling (dermatitis), rash, itching or swelling, particularly 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 narrowing of the visual field.
• severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis including pseudomembranous colitis), which in very rare cases may progress to life-threatening complications.
• recurrent nausea or vomiting, abdominal pain or excessive breathing.
• seizures or convulsions have been reported with Linezolid Krka. You must inform your doctor if you experience agitation, confusion, delirium, stiffness, tremor, lack of coordination or epileptic seizures, especially if you are also taking antidepressants known as SSRIs (see section 2).

Numbness, tingling and blurred vision have been reported in patients treated with Linezolid Krka for more than 28 days. If you experience vision problems, consult your doctor as soon as possible.
Other side effects include:
Common side effects (may affect up to 1 in 10 people):

• Fungal infections, particularly oral or vaginal candidiasis
• Headache
• Metallic taste in the mouth
• Diarrhoea, nausea and vomiting
• Changes in blood test results 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 affecting blood clotting or leading to anaemia
• Difficulty sleeping
• Increased blood pressure
• Anaemia (low red blood cell count)
• Changes in the number of certain blood cells which may affect the ability to fight infections
• Rash
• Itching
• Dizziness
• General or localized abdominal pain
• Constipation
• Indigestion
• Localized pain
• Fever

Uncommon side effects (may affect up to 1 in 100 people):

• Inflammation of the vagina or genital area in women
• Tingling or numbness sensation
• Blurred vision
• Ringing in the ears (tinnitus)
• Inflammation of the veins
• Dry or sore mouth, swollen, sore or discoloured tongue
• Pain at the site where the infusion (drip) is administered
• Inflammation of the veins (including at the infusion site (drip))
• 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
• Seizures
• Hyponatraemia (low sodium levels in the blood)
• Kidney failure
• Reduced platelet count
• Abdominal swelling
• Transient ischaemic attack (temporary disturbance in blood flow to the brain causing short-term symptoms such as loss of vision, weakness in arms and legs, confused speech and loss of consciousness)
• Pain at injection site
• Skin inflammation
• Increased creatinine
• Stomach ache
• Changes in heart rate (e.g. increased rhythm)

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

• Restricted visual field
• Superficial tooth discoloration, removable by dental cleaning (manual removal)

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

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

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via 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 stated on the pack and blister after
EXP. The expiry date refers to the last day of that month.
Do not store above 30°C.
Store in the original packaging to protect the medicine from light.
After first opening: chemical and physical stability have been demonstrated for 24 hours at room
temperature in the bag after removal of the secondary packaging (overwrap). From a
microbiological standpoint, the product should be used immediately. If not used immediately,
the 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, or if it ranges from colourless to yellow or brownish-yellow.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer used. This will help protect the environment.

6. Package contents and other information

What Linezolid Krka contains

• The active substance is linezolid. 1 ml of infusion solution contains 2 mg of linezolid. Each 300 ml infusion bag 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 or yellow-brown solution (pH: 4.6 – 5.2, osmolarity: 270 mOsmol/kg –
320 mOsmol/kg).
Linezolid infusion solution:
Primary packaging:
Multilayer plastic polyolefin bag (300 ml) with multilayer polyolefin plastic tube and removable polyolefin connector.
Secondary packaging:
Overpouch made of multilayer film. Film layers of the overpouch from outside to inside: polyester,
aluminium, polyester, propylene, 1 and 10 in a box.
Not all pack sizes may be marketed.
Marketing Authorization Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Local representative in Italy
Krka Farmaceutici Milano S.r.l. – Italy
This medicinal product is authorized in the European Economic Area countries under the
following names:

The following information is intended for healthcare professionals only:
Linezolid Krka 2 mg/ml infusion solution
Linezolid
IMPORTANT: See the Summary of Product Characteristics before prescribing.
Linezolid is not active against infections caused by Gram-negative pathogens. If the presence of Gram-negative pathogens is confirmed or suspected, concomitant specific therapy directed against these microorganisms must be initiated.

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

Dosage and method of administration
Linezolid must be administered only in a hospital setting 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 cases, no dosage adjustment is required, as the oral bioavailability of linezolid is approximately 100%.
The infusion solution must be administered over a period of 30 to 120 minutes.
The recommended dose should be administered intravenously twice daily.

Recommended dosage and duration of treatment for adults:
The duration of treatment depends on the causative pathogen, the site and severity of infection, and the patient's clinical response.
The following recommendations on treatment duration reflect those used in clinical studies.
Shorter treatment regimens may be suitable for certain 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 exceeding 28 days have not been established.
No dose increase or extension of treatment duration is required for infections associated with concomitant bacteraemia.
The recommended dosage for the infusion solution and for tablets/oral suspension granules is identical, as stated 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 become 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. creatinine clearance < 30 ml/min): no dosage modification is required. Since the clinical significance of higher exposure (up to 10-fold) to the two main metabolites of linezolid in patients with severe renal impairment is unknown, linezolid should be used with particular caution in these patients and only when the anticipated benefit is considered to outweigh the theoretical risk.
As approximately 30% of a dose of linezolid is removed during 3 hours of haemodialysis, Linezolid Krka should be administered after dialysis in patients undergoing haemodialysis. The main metabolites of linezolid are partially eliminated by haemodialysis, but their concentrations remain substantially higher after dialysis than those observed in patients with normal renal function or mild to moderate renal impairment. Linezolid should therefore be used with particular caution in patients with severe renal impairment undergoing haemodialysis, 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 other 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 via a non-enzymatic process, altered hepatic function is not expected to significantly affect its metabolism and therefore dose adjustment is not recommended. However, pharmacokinetic data and clinical experience with linezolid in patients with severe hepatic impairment are limited. Linezolid should be used with particular caution in patients with severe hepatic impairment and only when the anticipated benefit is considered to outweigh 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 any of these medicinal products.
Unless facilities are available for close monitoring and blood pressure surveillance, linezolid must not be administered to patients with the following clinical conditions or who are taking 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 medicinal products: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 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.

Breast-feeding must be discontinued before and during treatment.
Special warnings and precautions for use
Myelosuppression
Cases of myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) have been reported in patients treated with linezolid. In known outcome cases, abnormal haematological parameters returned towards pre-treatment levels after discontinuation of linezolid. The risk of these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid may be at increased risk of haematological disorders compared to younger patients. Thrombocytopenia may occur more commonly in patients with severe renal impairment, whether or not on dialysis. Therefore, careful monitoring of blood counts is recommended in patients with: pre-existing anaemia, granulocytopenia or thrombocytopenia; those receiving concomitant medicinal products that may reduce haemoglobin levels, suppress blood counts or have adverse effects on platelet count or function; those with severe renal impairment; or those receiving linezolid for more than 10–14 days. In such patients, linezolid should be administered only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible.
If significant myelosuppression occurs during treatment with linezolid, treatment should be discontinued unless continuation is considered absolutely necessary; in such cases, intensive monitoring of blood counts and appropriate therapeutic measures should be initiated.
Weekly monitoring of full blood count (including haemoglobin levels, platelets, and total and differential white blood cell count) is also recommended in patients receiving linezolid, regardless of baseline blood counts.
In compassionate use studies, a higher incidence of severe anaemia has been reported in patients treated with linezolid for periods exceeding the maximum recommended duration of 28 days. Blood transfusions were more frequently required in these patients. Cases of anaemia requiring transfusion have also been reported in post-marketing experience, with a higher incidence in patients treated with linezolid for more than 28 days.
In post-marketing experience, cases of sideroblastic anaemia have been reported. In cases where onset time 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 treatment for anaemia.
Imbalance in mortality rate in a clinical study in patients with Gram-positive catheter-related bacteraemia
In an open-label clinical study in critically ill patients with intravascular catheter-related infections, a higher mortality rate was observed in patients treated with linezolid compared to vancomycin, dicloxacillin or oxacillin [78/363 (21.5%) versus 58/363 (16.0%)]. The main factor influencing mortality rate was the baseline severity of Gram-positive infection. 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 among patients who had other pathogens or no pathogens at baseline (odds ratio 2.48; 95% confidence interval: 1.38–4.46). The greatest difference occurred during treatment and within 7 days of treatment discontinuation. A higher number of patients in the linezolid arm developed infections with Gram-negative pathogens during the study, and patients died from Gram-negative and polymicrobial infections. Therefore, in complicated skin and soft tissue infections, linezolid should be used in patients with known or suspected concomitant Gram-negative pathogen infections only when no other therapeutic alternatives are available. In such circumstances, concomitant therapy against Gram-negative pathogens should be initiated.
Antibiotic-associated diarrhoea and colitis
Antibiotic-associated diarrhoea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhoea during or after use of linezolid.
If antibiotic-associated diarrhoea or colitis is suspected or confirmed, ongoing antibacterial therapy, including linezolid, should be discontinued and appropriate therapeutic measures should be initiated immediately. In this situation, antiperistaltic agents are contraindicated.
Lactic acidosis
Cases of lactic acidosis have been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis during treatment with linezolid, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation, should receive immediate medical attention. If lactic acidosis occurs, the benefits of continuing linezolid therapy should be weighed against potential risks.
Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. As a consequence of this inhibition, adverse events such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur; these events are more common when the drug is used for more than 28 days.
Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with concomitant administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Concomitant administration of linezolid and serotonergic agents is therefore contraindicated, except in cases where concomitant administration is essential. In such cases, patients must be closely monitored for signs and symptoms of serotonin syndrome, such as changes in cognitive function, hyperthermia, hyperreflexia and lack of coordination. If these signs and symptoms occur, the physician must consider discontinuing one or both concomitant therapies; if the serotonergic agent is discontinued, withdrawal symptoms may occur.
Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis, have been reported in patients receiving linezolid therapy, sometimes progressing to vision loss; these cases have occurred primarily in patients treated for periods exceeding the maximum recommended duration of 28 days.
All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, altered colour vision, blurred vision or visual field defects. In such cases, timely ophthalmological examination is recommended, and referral to an ophthalmologist if necessary. In cases of linezolid treatment exceeding the maximum recommended duration of 28 days, regular monitoring of visual function should be performed in all patients.
If peripheral or optic neuropathy occurs, continuation of linezolid therapy should be evaluated against potential risks.
The risk of neuropathy may increase when linezolid is used in patients who are concomitantly taking or have recently taken antimycobacterial agents for the treatment of tuberculosis.
Seizures
Cases of seizures have been reported in patients receiving linezolid. In most cases, a history of epilepsy or risk factors for seizures was reported. In patients with a history of seizures, they should be advised to inform their physician.
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO); however, at doses used for antibacterial therapy, 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 concomitant therapies that may pose a risk due to MAO inhibition. Therefore, the use of linezolid is not recommended in these circumstances unless close monitoring and surveillance are possible.
Use with tyramine-rich foods
Patients should be advised not to consume large quantities of tyramine-rich foods.
Superinfections
Clinical studies have not evaluated the effects of linezolid therapy on normal flora. Antibiotic use may occasionally lead to overgrowth of non-susceptible microorganisms. For example, approximately 3% of patients treated with the recommended dose of linezolid developed drug-related candidiasis during clinical studies. Appropriate measures should be taken if superinfection occurs during therapy.
Special populations
Linezolid should be used with particular caution in patients with severe renal impairment and only when the anticipated benefit is considered to outweigh the theoretical risks.
Linezolid should be administered in patients with severe hepatic impairment only when the anticipated benefit outweighs the theoretical risk.
Impairment of fertility
Linezolid has reversibly reduced fertility and induced morphological abnormalities in sperm of 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 exceeding 28 days have not been established.
Controlled clinical studies did not include patients with diabetic foot lesions, pressure ulcers, ischaemic wounds, 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 hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency must not take this medicine.
300 ml of solution also contain 114 mg of sodium (5 mmol). The sodium content should be taken into account in patients on a low-sodium diet.
Interactions
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). Very limited data are available from drug interaction studies and on the safety of linezolid administered to patients receiving concomitant medications that may pose a risk due to MAO inhibition. Therefore, the use of linezolid is not recommended in these circumstances unless close monitoring and surveillance are possible.
Potential interactions leading to increased blood pressure
In healthy normotensive volunteers, linezolid potentiated the blood pressure increase induced by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of 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. Similar studies have not been conducted in hypertensive subjects. Careful titration of vasopressor agents, including dopaminergic substances, is recommended to achieve the desired response when administered concomitantly with linezolid.
Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects received dextromethorphan (two 20 mg doses administered 4 hours apart), with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, erythema, diaphoresis, hyperthermia) were observed in normal subjects treated with linezolid and dextromethorphan.
Post-marketing experience: A report has been documented of a patient who developed symptoms resembling serotonin syndrome during concomitant use of linezolid and dextromethorphan, which resolved upon discontinuation of both treatments.
In clinical experience with concomitant use of linezolid and serotonergic agents, including antidepressants such as serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been reported. Concomitant administration is therefore contraindicated, but management of patients for whom concomitant treatment with linezolid and serotonergic agents is essential is described in the section "Special warnings and precautions for use".
Use with tyramine-rich foods
Subjects treated with linezolid and less than 100 mg of tyramine did not show any significant pressor response. This indicates that only excessive intake of foods and beverages high in tyramine (e.g., aged cheese, yeast extracts, non-distilled alcoholic beverages and fermented soy products such as soy sauce) should be avoided.
Drugs metabolised by cytochrome P450
Linezolid is not significantly metabolised by the cytochrome P450 (CYP) enzyme system and does not inhibit any of the clinically significant isoforms of human CYP (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-mediated drug interactions with linezolid are expected.
Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers who received linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin reduced the 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 was co-administered with linezolid under steady-state conditions, a 10% reduction in mean maximum INR and a 5% reduction in INR AUC were observed during concomitant administration. The clinical significance of these findings, if any, cannot be determined due to insufficient data from patients treated with warfarin and linezolid.
Fertility, pregnancy and breast-feeding
Pregnancy
Adequate data on the use of linezolid in pregnant women are not available. Animal studies have shown toxic effects on reproduction. A potential risk to humans exists.
Linezolid must not be used during pregnancy unless strictly necessary, i.e. only when the expected benefits outweigh the theoretical risk.
Breast-feeding
Animal data indicate that linezolid and its metabolites may pass into breast milk and, consequently, breast-feeding must be discontinued before and during administration.
Fertility
In animal studies, linezolid caused a reduction in fertility.
Effects on ability to drive and use machines
Patients should be informed of the potential occurrence of dizziness or visual disturbances during treatment with linezolid, and should therefore be advised not to drive or operate machinery if any of these symptoms occur.
Undesirable effects
The table below lists adverse drug reactions that occurred with frequency based on all-cause data from clinical studies involving over 2,000 adult patients treated for up to 28 days with the recommended doses of linezolid. The 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 leading to treatment discontinuation were headache, diarrhoea, nausea and vomiting. Approximately 3% of patients discontinued treatment due to a drug-related adverse event.
Additional adverse reactions reported during post-marketing experience are included in the table under the category "not known", as the available data do not allow determination of the actual frequency.
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 (frequency cannot be estimated from the available data).

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

Overdose
No specific antidote is known.
Cases of overdose have not been reported. The following information may nevertheless be useful:
Supportive treatment is recommended, together with maintenance of glomerular filtration. Approximately 30% of a dose of linezolid is removed during 3 hours of haemodialysis, but no data are available on the elimination of linezolid by peritoneal dialysis or haemoperfusion. The two major metabolites of linezolid are also partially removed by haemodialysis.

Instructions for use and handling
For single use only. Remove the outer wrapper only when ready for use, then check for leaks by firmly squeezing the bag. If leakage from the bag is observed, do not use, as sterility may be compromised. The solution should be inspected visually prior to use and only clear solutions without particles should be used. Do not use bags connected in series. Unused solution must be discarded. No special requirements for disposal. Any unused medicine or waste material derived from this medicine must be disposed of in accordance with local regulations. Do not reconnect partially used bags.
Linezolid Krka infusion solution is compatible with the following solutions: 5% glucose for intravenous infusion, 0.9% sodium chloride for intravenous infusion, Ringer's lactate solution for injectable preparations (Hartmann's solution for injection).

Incompatibilities
Additives should not be introduced into this solution. If linezolid is to be administered in combination with other medicinal products, each medicinal product must be administered separately according to its instructions for use. Similarly, if the same intravenous line is to be used for the sequential infusion of different medicinal products, the line must be flushed before and after administration of linezolid with a compatible infusion solution.
Linezolid infusion solution is known to be physically incompatible with the following compounds: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin and sulfamethoxazole/trimethoprim. In addition, 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 container (bag) after removal of the secondary packaging (overpouch). From a microbiological standpoint, the product should be used immediately. If not used immediately, the times and conditions of storage prior to use are the responsibility of the user.

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