Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

Linezolid Kabi 2 mg/ml infusion solution EFG

Read the entire leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• If you experience any adverse reactions, consult your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet:

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

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

Linezolid Kabi 2 mg/ml is an antibiotic belonging to the oxazolidinone group that works by inhibiting the growth of certain types of bacteria (germs) that cause infections.

Antibiotics are used to treat bacterial infections and are not effective against viral infections such as influenza or the common cold.

It is important that you follow your doctor's instructions regarding dosage, dosing interval, and duration of treatment.

Do not store or reuse this medicine. If you have any antibiotic left over after completing your treatment, return it to the pharmacy for proper disposal. Do not dispose of medicines via wastewater or household waste.

It is used to treat pneumonia and certain skin or subcutaneous tissue infections. Your doctor will decide whether Linezolid Kabi 2 mg/ml is appropriate for treating your infection.

2. What you need to know before using Linezolid Kabi

Do not use Linezolid Kabi

• 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 medicine belonging to the class of monoamine oxidase inhibitors (MAOIs, e.g., phenelzine, isocarboxazide, selegiline, moclobemide). You may have been prescribed these medicines to treat depression or Parkinson's disease.
• if you are breastfeeding. The reason is that linezolid passes into breast milk and may affect the infant.

Warnings and Precautions

Talk to your doctor, pharmacist, or nurse before starting to use Linezolid Kabi.

Linezolid Kabi 2 mg/ml may not be suitable for you if you answer yes to any of the following questions. In such cases, inform your doctor, who may need to assess your general health and blood pressure before and during treatment, or decide whether another treatment would be more appropriate for you.

Ask your doctor if you are unsure whether any of these categories apply to you.

• Do you have high blood pressure, regardless of whether you are taking medication for it?
• Have you been diagnosed with overactive thyroid (hyperthyroidism)?
• Do you have a tumor of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumors of the hormonal system, with symptoms such as diarrhea, skin flushing, and wheezing)?
• Do you suffer from bipolar disorder, schizoaffective disorders, confusion, or other mental health problems?
• Do you have a history of hyponatremia (low sodium levels in the blood), or are you taking medicines that reduce sodium levels in the blood, such as certain diuretics like hydrochlorothiazide?
• Are you taking opioids?

Using certain medicines, including antidepressants and opioids, together with linezolid may lead to serotonin syndrome, a potentially life-threatening condition (see section 2 “Use of Linezolid Kabi with other medicines” and section 4).

Take special care with Linezolid Kabi

Talk to your doctor before starting Linezolid Kabi 2 mg/ml if:

• You are elderly
• you bruise easily or bleed excessively
• you are anemic (low red blood cell count)
• you are prone to infections
• you have a history of epileptic seizures
• you have liver or kidney problems, especially if you are on dialysis
• you have diarrhea

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

• visual problems such as blurred vision, changes in color vision, difficulty seeing fine details, or narrowing of your field of vision.
• loss of sensation in your arms or legs, or a tingling or prickling sensation in your arms or legs.
• diarrhea, which may occur if you are taking or have taken antibiotics, including Linezolid Kabi 2 mg/ml. If diarrhea becomes severe or persistent, or if you notice blood or mucus in your stools, stop treatment with Linezolid Kabi 2 mg/ml immediately and consult your doctor. In such cases, do not take medicines that inhibit or slow down intestinal motility.
• repeated nausea or vomiting, abdominal pain, or hyperventilation.
• unexplained muscle pain, tenderness, or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• malaise and dizziness with muscle weakness, headache, confusion, and memory impairment, which may indicate hyponatremia (low sodium levels in the blood).

Use of Linezolid Kabi with other medicines

There is a risk that Linezolid Kabi may interact with other medicines, causing adverse reactions such as changes in blood pressure, body temperature, or heart rate.

Inform your doctor or pharmacist if you are taking or have recently taken any other medicine.

Inform your doctor if you are taking or have taken any of the following medicines within the last 2 weeks, as Linezolid Kabi must not be taken if you are already taking these medicines or have taken them recently (see also section 2, "Do not use Linezolid Kabi"):

• medicines that may inhibit monoamine oxidase (MAOIs, e.g., phenelzine, isocarboxazide, selegiline, moclobemide). You may have been prescribed these medicines 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 Kabi, but will need to assess your general health and blood pressure before and during treatment. In other cases, your doctor may decide to prescribe a different treatment more suitable for you.

• nasal decongestants or cold remedies containing pseudoephedrine or phenylpropanolamine.
• certain asthma medicines such as salbutamol, terbutaline, fenoterol.
• certain antidepressants such as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many of these, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• medicines for migraine, such as sumatriptan and zolmitriptan.
• medicines for treating severe and sudden allergic reactions, such as adrenaline (epinephrine).
• medicines that increase blood pressure, such as noradrenaline (norepinephrine), dopamine, and dobutamine.
• opioids (e.g., meperidine) used to treat moderate to severe pain.
• medicines for anxiety disorders, such as buspirone.
• medicines that prevent blood clotting, such as warfarin.
• an antibiotic called rifampicin.

Use of Linezolid Kabi with food and drink

• You may use Linezolid Kabi before, during, or after meals.
• Avoid consuming large amounts of aged cheese, yeast extracts, soy extracts (such as soy sauce), and alcoholic beverages, especially draught beer and wine. The reason is that linezolid may react with a substance called tyramine present in certain foods. This interaction may cause an increase in your blood pressure.
• If you develop a throbbing headache after eating or drinking, inform your doctor or pharmacist immediately.

Pregnancy, breastfeeding, and fertility

The effects of Linezolid Kabi in pregnant women are unknown. Therefore, it should not be used during pregnancy unless advised by your doctor. If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

You must not breastfeed while using Linezolid Kabi, as it passes into breast milk and may affect the infant.

Driving and use of machines

Linezolid Kabi may cause dizziness or visual disturbances. If this occurs, do not drive or operate machinery. Remember that if you feel unwell, your ability to drive or operate machinery may be impaired.

Linezolid Kabi contains glucose

This medicine contains glucose.

Patients with diabetes mellitus should be aware that this medicine contains 45.7 mg of glucose per ml of solution (13.7 g in a bag).

Linezolid Kabi contains sodium

Patients on low-sodium diets should be aware that each 1 ml of Linezolid Kabi contains 0.38 mg of sodium (main component of table/cooking salt) (114 mg of sodium in a bag). The sodium content in one bag corresponds to 5.7% of the maximum recommended daily sodium intake for an adult.

3. How to use Linezolid Kabi

Follow exactly the instructions for administration of this medicine as given by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist again.

Adults

This medicine will be administered to you by a doctor or other healthcare professional as a drip (by infusion into a vein).

The recommended dose for adults (18 years of age or older) is 300 ml (600 mg of linezolid) twice daily administered directly into the bloodstream (intravenously) by infusion over a period of 30 to 120 minutes.

If you are undergoing dialysis, Linezolid Kabi will be administered after each dialysis session.

A treatment course usually lasts 10 to 14 days, but may extend up to 28 days. The safety and efficacy of this medicine have not been established for periods longer than 28 days. Your doctor will decide the duration of treatment.

During treatment with Linezolid Kabi, your doctor should periodically perform blood tests to monitor your blood count.

Your doctor should monitor your vision if you are using Linezolid Kabi for longer than 28 days.

Use in children and adolescents

Linezolid Kabi is not normally used in children and adolescents (under 18 years of age).

If you use more Linezolid Kabi than you should

If you think you may have been given more Linezolid Kabi than you should have, inform your doctor or nurse.

In case of overdose or accidental ingestion, consult your doctor or pharmacist or call the Toxicology Information Service at telephone number: 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to use Linezolid Kabi

Since this medicine is administered under close supervision, it is very unlikely that a dose will be missed. If you think a dose of your treatment has been forgotten, inform your doctor or nurse. Do not take a double dose to make up for a missed dose.

4. Possible adverse effects

Like all medicines, Linezolid Kabi may cause adverse effects, although not everyone experiences them.

Immediately inform your doctor or pharmacist if you experience any of the following adverse effects during treatment with Linezolid Kabi:

The most serious adverse effects (with frequency in parentheses) of Linezolid Kabi are:

• Severe skin reactions (uncommon), swelling, particularly around the face and neck (uncommon), wheezing and/or difficulty breathing (rare). These may be signs of an allergic reaction, and treatment with Linezolid Kabi may need to be stopped. Skin reactions such as raised purple rash due to inflammation of blood vessels (rare), red, peeling skin lesions (dermatitis) (uncommon), skin rash (common), itching (common).
• Visual disturbances (uncommon), such as blurred vision (uncommon), changes in color perception (frequency not known), difficulty seeing fine details (frequency not known), or narrowing of the visual field (rare).
• Severe diarrhea, with blood and/or mucus in the stool (antibiotic-associated colitis, including pseudomembranous colitis), which in rare circumstances may lead to potentially life-threatening complications (uncommon).
• Nausea or repeated vomiting, abdominal pain, or rapid breathing (rare).
• Seizures or epileptic fits have been reported (uncommon).
• Serotonin syndrome (frequency not known): inform your doctor if you experience agitation, confusion, delirium, muscle rigidity, tremors, lack of coordination, seizures, rapid heartbeat, severe breathing problems, or diarrhea (suggestive of serotonin syndrome) while taking antidepressants such as SSRIs or opioids concomitantly (see section 2).
• Unexplained bleeding or bruising, which may be due to changes in the number of certain blood cells affecting blood clotting or causing anemia (common).
• Changes in the number of certain blood cells that may affect the ability to fight infections (uncommon). Some signs of infection include: fever (common), sore throat (uncommon), mouth ulcers (uncommon), and fatigue (uncommon).
• Rhabdomyolysis (rare): signs and 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 can lead to kidney damage. Pancreatitis (uncommon).
• Seizures (uncommon).
• Transient ischaemic attacks (temporary disruption of blood flow to the brain causing short-term symptoms such as loss of vision, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
• Ringing in the ears (tinnitus) (uncommon).

Numbness, tingling, or blurred vision are other adverse effects reported in patients treated with Linezolid Kabi for more than 28 days. If you experience vision problems, consult your doctor as soon as possible.

Other adverse effects include:

Common (may affect up to 1 in 10 people)

• Fungal infections, especially vaginal or oral
• Headache
• Metallic taste in the mouth
• Diarrhea, nausea, or vomiting
• Changes in certain blood test results, including tests for proteins, salts, or enzymes measuring kidney or liver function or blood glucose concentration
• Difficulty sleeping
• Increased blood pressure
• Anemia (low red blood cells)
• Dizziness
• Localized or generalized abdominal pain
• Constipation
• Indigestion
• Localized pain
• Reduced platelet count

Uncommon (may affect up to 1 in 100 people)

• Vaginal or genital area inflammation in women
• Tingling or numbness sensations
• Swollen, painful, or discolored tongue
• Dry mouth
• Pain at or around the injection site
• Vein inflammation (including at the site where the infusion line is placed)
• Frequent need to urinate
• Chills
• Thirst sensation
• Increased sweating
• Hyponatremia (low sodium levels in blood)
• Kidney failure
• Abdominal swelling
• Pain at injection site
• Increased creatinine
• Stomach pain
• Changes in heart rhythm (e.g., increased heart rate)
• Decreased blood cell counts
• Weakness and/or sensory changes

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

• Change in tooth surface coloration, which may be removed by professional dental cleaning (tartrectomy)

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

• Alopecia (hair loss)

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Linezolid Kabi

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

Freeflex bag: Do not use this medicine after the expiry date stated on the bag, outer bag, and outer packaging following EXP. The expiry date refers to the last day of the month indicated.

Healthcare professionals will ensure that Linezolid Kabi is not used beyond the "Use by" date printed on the bag and that it is administered as soon as the seal is broken. They will also visually inspect the solution before use and administer it only if it is clear and free from particles. Store the outer bag in the original packaging to protect it from light until preparation.

KabiPac vial: Do not use this medicine after the expiry date stated on the vial and outer packaging following EXP. The expiry date refers to the last day of the month indicated.

Hospital staff will ensure that Linezolid Kabi is not used beyond the "Use by" date printed on the vial and that it is administered as soon as it is removed from the outer packaging. They will also visually inspect the solution before use and administer it only if it is clear and free from particles. They will also ensure that the solution is properly stored in its outer packaging to protect it from light and kept out of the sight and reach of children until required.

After opening

Physical and chemical stability in use has been demonstrated for 24 hours at 2–8°C.

From a microbiological standpoint, unless the opening procedure excludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the duration and conditions of in-use storage are the responsibility of the user.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Linezolid Kabi

• The active substance is linezolid. Each 1 ml of solution contains 2 mg of linezolid.
• The other components are monohydrate glucose (a type of sugar), sodium citrate, citric acid, hydrochloric acid or sodium hydroxide, and water for injections.

Appearance of Linezolid Kabi and contents of the pack

Freeflex bag:

Linezolid Kabi is presented as a clear solution, practically free from particles, colourless or yellowish, in single-dose infusion bags containing 300 ml (600 mg of linezolid) of solution.

The bags are supplied in cartons of 10, 30 or 50 bags.

KabiPac vial:

Linezolid Kabi is presented as a clear solution, practically free from particles, colourless or yellowish or slightly brown, in single-dose infusion vials containing 300 ml (600 mg of linezolid) of solution.

The vials are supplied in cartons of 10, 30 or 50 vials.

Only certain pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Fresenius Kabi España, S.A.U.

Marina 16-18,

08005 Barcelona

Spain

Manufacturer

Fresenius Kabi Norge AS

Svinesundsveien 80,

NO-1788 Halden

Norway

This medicinal product is authorised in the European Economic Area Member States and in the United Kingdom (Northern Ireland) under the following names:

Date of the most recent review of this package leaflet:

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

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This information is intended for healthcare professionals only:

Linezolid Kabi 2 mg/ml solution for infusion

IMPORTANT: Consult the summary of product characteristics before prescribing.

Linezolid has no activity against infections caused by Gram-negative microorganisms. Specific treatment against such microorganisms should be initiated concomitantly if a Gram-negative organism is documented or suspected.

Description of Freeflex bags:

Freeflex infusion bags, multilayer polyolefin, latex-free, single-use, ready-to-use, sealed within an outer laminated aluminum bag. The bag contains 300 ml of solution and is packaged in a carton. Each carton contains 10, 30, or 50 infusion bags.

Linezolid Kabi contains linezolid 2 mg/ml in an isotonic, clear, practically particle-free solution, ranging from colourless to yellowish. The other ingredients are: monohydrate glucose, sodium citrate, citric acid, hydrochloric acid or sodium hydroxide, and water for injections.

Description of KabiPac bottles:

KabiPac bottles, made of polyethylene, single-use, ready-to-use, closed with a stopper containing a rubber disc allowing needle insertion. The bottle contains 300 ml of solution and is packaged in a carton. Each carton contains 10, 30, or 50 infusion bottles.

Linezolid Kabi contains linezolid 2 mg/ml in an isotonic, clear, particle-free solution, ranging from colourless to yellowish or slightly brown. The other ingredients are: monohydrate glucose, sodium citrate, citric acid, hydrochloric acid or sodium hydroxide, and water for injections.

Posology and method of administration

Linezolid should only be initiated in a hospital setting and after consultation with an appropriate specialist such as a microbiologist or an infectious disease specialist. Patients starting treatment with the parenteral formulation may be switched to any of the oral formulations when clinically indicated. In such cases, no dose 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 of linezolid should be administered intravenously (IV) twice daily.

Recommended doses and duration of treatment in 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 trials. Shorter treatment regimens may be appropriate for certain types of infection, although they have not been evaluated in clinical trials.

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.

There is no need to increase the recommended dose or duration of treatment for infections associated with concurrent bacteraemia.

The following dosage recommendations apply:

Paediatric population

The safety and efficacy of linezolid in children under 18 years of age have not been established. The currently available data are described in sections 4.8, 5.1 and 5.2 of the product characteristics summary; however, no dosage recommendation can be made.

Elderly patients: No dose adjustments are required.

Renal impairment: No dose adjustment is required.

Severe renal impairment (i.e., creatinine clearance [CrCl] < 30 mL/min)

No dose adjustments are 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 caution in these patients and only when the expected benefits outweigh the theoretical risk.

As approximately 30% of the dose of linezolid is removed during 3 hours of haemodialysis, linezolid should be administered only after dialysis in such patients. The main metabolites of linezolid are partially removed during haemodialysis, although their concentrations remain considerably higher after dialysis than those observed in patients with normal renal function or mild to moderate renal impairment.

Therefore, linezolid should be used with special caution in patients with severe renal impairment undergoing dialysis and only when the expected benefits outweigh the theoretical risk.

To date, there is no experience with administration of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal impairment (other than haemodialysis).

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

Severe hepatic impairment (Child-Pugh class C): As linezolid is metabolized by a non-enzymatic process, hepatic impairment is not expected to significantly alter its metabolism and therefore dose adjustments are not recommended. However, sufficient clinical data are not available and it is recommended that linezolid be used in these patients only when the expected benefit is considered to outweigh the theoretical risk (see sections 4.4 and 5.2 of the summary of product characteristics).

Contraindications

Hypersensitivity to linezolid or to any of the excipients.

Linezolid must not be used in patients receiving monoamine oxidase inhibitors A or B (such as phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks after discontinuation of these medications. Unless facilities for strict monitoring and blood pressure control are available, linezolid must not be administered to patients with the following underlying conditions or under the following concomitant treatments:

• Patients with untreated hypertension, phaeochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, schizoaffective disorders, or acute confusional states.
• Patients receiving any of the following drugs: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressors (such as epinephrine and norepinephrine), dopaminergic agents (such as dopamine and dobutamine), meperidine or buspirone.

Breastfeeding must be discontinued before and during treatment (see section 4.6 of the summary of product characteristics).

Warnings and precautions for use

Myelosuppression

Cases of myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) have been reported in patients treated with linezolid. In patients who were monitored, affected haematological parameters were observed to increase towards pre-treatment levels after discontinuation of therapy. The risk of these effects appears to be associated with the duration of treatment. Elderly patients receiving linezolid may be at increased risk of developing blood dyscrasias compared to younger patients. Thrombocytopenia may occur more frequently in patients with severe renal impairment, whether or not undergoing dialysis, and in patients with moderate to severe hepatic impairment. Therefore, close monitoring of the full blood count is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; receive concomitant medications that may decrease haemoglobin levels and red blood cell count or reduce or adversely affect platelet count or function; have severe renal impairment or moderate to severe hepatic impairment; or receive more than 10–14 days of treatment.

Linezolid should only be administered to these patients if 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, haematological parameters should be closely monitored and appropriate therapeutic measures implemented.

Additionally, a complete weekly blood count (including haemoglobin, platelets, absolute leucocyte count and differential) is recommended for all patients receiving linezolid, regardless of baseline haematological parameters.

In compassionate use studies, a higher incidence of severe anaemia was reported in patients treated with linezolid for periods exceeding the maximum recommended treatment duration of 28 days. These patients more frequently required blood transfusion. Post-marketing experience has also reported cases of anaemia requiring blood transfusion, with a higher number of cases in patients who received linezolid for more than 28 days.

Cases of sideroblastic anaemia have been reported during post-marketing experience. In cases where onset time was known, most patients had been treated for more than 28 days. Most patients recovered fully or partially after discontinuation of linezolid treatment, with or without treatment for anaemia.

Imbalance in mortality in a clinical trial in patients with Gram-positive catheter-related vascular infections

In an open-label study in critically ill patients with catheter-related vascular infections, an excess mortality was observed in patients treated with linezolid compared to those treated with vancomycin/dicloxacillin/oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing mortality rate was baseline infection with Gram-positive organisms. Mortality rates were similar in patients with infections caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58–1.59), but significantly higher (p = 0.0162) in the linezolid arm for patients infected with any other microorganism or in whom no baseline microorganism was isolated (odds ratio 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the study drug. In the linezolid arm, more patients acquired infections with Gram-negative microorganisms during the study and died from infections caused by Gram-negative microorganisms and polymicrobial infections. Therefore, linezolid should only be used in patients with complicated skin and soft tissue infections in whom co-infection with Gram-negative microorganisms is suspected or confirmed if no other alternative treatments are available. In such circumstances, concomitant therapy against Gram-negative microorganisms should be initiated.

Diarrhoea and antibiotic-associated colitis

Cases of antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridioides difficile-associated diarrhoea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhoea to fatal colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhoea during or after treatment with linezolid. If antibiotic-associated diarrhoea or colitis is suspected or confirmed, antibacterial agents, including linezolid, should be discontinued and appropriate therapeutic measures initiated immediately. Medications that inhibit peristalsis are contraindicated in this situation.

Lactic acidosis

Cases of lactic acidosis have been reported with the use of linezolid. Patients who develop signs or symptoms of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation while receiving linezolid 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 result of this inhibition, adverse events such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur; these events are more frequent when treatment duration exceeds 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) and opioids, have been reported (see section 4.5 of the summary of product characteristics). Therefore, concomitant administration of linezolid and serotonergic agents is contraindicated (see section 4.3 of the summary of product characteristics), unless administration of linezolid and serotonergic agents is absolutely necessary. In such cases, patients should be carefully observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperthermia, hyperreflexia and incoordination. If signs or symptoms occur, discontinuation of one or both agents should be considered; if the serotonergic agent is discontinued, symptoms may resolve.

Rhabdomyolysis

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

Hyponatraemia and SIADH

Hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients treated with linezolid. Serum sodium levels should be monitored regularly in patients at risk of hyponatraemia, such as elderly patients or patients taking medications that may reduce blood sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).

Optic and peripheral neuropathy

Cases of peripheral neuropathy, as well as optic neuropathy and optic neuritis, occasionally progressing to vision loss, have been reported in patients treated with linezolid; these cases have mainly occurred in patients treated for periods exceeding the maximum recommended duration of 28 days.

All patients should be advised to report symptoms of visual disturbance, such as changes in visual acuity, changes in colour vision, blurred vision or visual field defects. In such cases, visual function should be evaluated as soon as possible and an ophthalmologist consulted if necessary. Visual function should be monitored regularly in any patient treated with linezolid for longer than the recommended 28 days.

Continuation of treatment with linezolid in patients who have developed optic or peripheral neuropathy should be evaluated against potential risks.

An increased risk of neuropathies may exist when linezolid is used in patients currently receiving or who have recently received antimycobacterial medication for the treatment of tuberculosis.

Seizures

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

Monoamine oxidase inhibitors

Linezolid is a reversible and non-selective monoamine oxidase inhibitor (MAOI); however, it has no antidepressant effect at doses used for antibacterial treatment. There is limited data from pharmacological interaction and safety studies of linezolid in patients receiving concomitant medications and/or with underlying conditions that increase this risk. Therefore, linezolid is not recommended in such circumstances unless close observation and monitoring of the patient are possible.

Use with tyramine-rich foods

Patients should be advised not to consume large quantities of tyramine-rich foods.

Superinfection

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

Occasionally, the use of antibacterials may lead to overgrowth of non-susceptible microorganisms. Approximately 3% of patients who received linezolid at the recommended doses in clinical trials developed treatment-associated candidiasis. In cases of superinfection during treatment, appropriate measures should be taken.

Special populations

Linezolid should be used with special caution in patients with severe renal impairment, and only if the expected benefit outweighs the potential risk (see sections 4.2 and 5.2).

It is recommended that linezolid be administered to patients with severe hepatic impairment only if the expected benefit outweighs the potential risk.

Effects on fertility

In studies conducted in adult male rats with exposure levels to linezolid similar to those expected in humans, a reversible decrease in fertility and abnormal sperm morphology were observed. The potential effects of linezolid on the human male reproductive system are unknown.

Clinical trials

The safety and efficacy of linezolid have not been established when administered for periods longer than 28 days.

Controlled clinical trials did not include patients with diabetic foot lesions, pressure ulcers, ischaemic lesions, severe burns or gangrene. Therefore, experience with the use of linezolid in the treatment of these conditions is limited.

Excipients

Glucose

This medicinal product contains 45.7 mg of glucose per mL of solution (13.7 g/300 mL), which should be taken into account when treating patients with diabetes mellitus or other conditions associated with glucose intolerance.

Sodium

This medicinal product contains 0.38 mg of sodium per mL of solution (114 mg/300 mL), equivalent to 0.02 of the maximum recommended daily intake (RDI) of 2 g of sodium by the WHO for an adult, which should be taken into account when treating patients on low-sodium diets.

Linezolid infusion solution may be prepared for administration with solutions containing sodium (see sections 4.2, 6.2 and 6.6), and this should be considered in relation to the total sodium from all sources to be administered to the patient.

Interactions

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Data from pharmacological interaction and safety studies of linezolid administered to patients receiving concomitant treatments with risk of MAO inhibition are very limited. Therefore, linezolid is not recommended in these circumstances unless close observation and monitoring of the patient are possible.

Potential interactions causing increased blood pressure

Linezolid increased the hypertensive effect of pseudoephedrine and phenylpropanolamine hydrochloride in healthy normotensive volunteers. Simultaneous administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride produced mean increases in systolic blood pressure of 30–40 mmHg, compared with 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 patients. It is recommended that if linezolid is administered with vasopressor drugs (including dopaminergic agents), their doses should be carefully titrated to achieve the desired response.

Potential serotonergic interactions

In healthy volunteers, the potential for pharmacological interaction between linezolid and dextromethorphan was studied. Two doses of 20 mg dextromethorphan were administered 4 hours apart, with or without linezolid. In healthy subjects receiving linezolid and dextromethorphan, no effects of serotonin syndrome (confusion, delirium, restlessness, tremor, flushing, diaphoresis, hyperthermia) were observed.

During post-marketing experience: a case of a patient experiencing symptoms similar to serotonin syndrome while taking linezolid and dextromethorphan was reported, which resolved upon discontinuation of both treatments.

Cases of serotonin syndrome have been reported during clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, as concomitant administration is contraindicated (see section 4.3 of the summary of product characteristics), management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary.

Use with tyramine-rich foods

No significant pressor response was observed in subjects who received linezolid and less than 100 mg of tyramine. This suggests that only excessive intake of foods or beverages high in tyramine (e.g., aged cheese, yeast extracts, non-distilled alcoholic beverages and fermented soy products such as soy sauce) needs to be avoided.

Drugs metabolized via the cytochrome P450 system

Linezolid is not detectably metabolized by the cytochrome P450 (CYP) enzyme system and does not inhibit any clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, CYP450-mediated pharmacological interactions with linezolid are not expected.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult males who received 600 mg of linezolid twice daily for 2.5 days, with and without 600 mg of rifampicin once daily for 8 days. Rifampicin decreased 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 relevance are unknown.

Warfarin

Concomitant administration of warfarin and linezolid (at steady state) resulted in a 10% reduction in mean maximum INR (International Normalized Ratio) and a 5% decrease in INR AUC. Data from patients receiving warfarin and linezolid are insufficient to evaluate the clinical relevance, if any, of these findings.

Fertility, pregnancy and lactation

Pregnancy

Data on the use of linezolid in pregnant women are limited. Animal studies have shown reproductive toxicity. There is a potential risk in humans.

Linezolid should not be used during pregnancy unless clearly necessary. That is, only if the potential benefit outweighs the possible risk.

Lactation

Animal data suggest that linezolid and its metabolites may pass into breast milk; therefore, breastfeeding must be discontinued before and during treatment.

Fertility

In animal studies, linezolid caused a reduction in fertility.

Effects on ability to drive and use machines

Patients should be advised that they may experience dizziness or visual disturbances while receiving linezolid, and should be advised not to drive or operate machinery if either of these symptoms occurs.

Adverse reactions

The following table lists all adverse drug reactions with a frequency based on all causality data from clinical trials involving more than 2,000 adult patients who received the recommended doses of linezolid for up to 28 days.

The most frequently reported adverse reactions were diarrhoea (8.9%), nausea (6.9%), vomiting (4.3%) and headache (4.2%).

The drug-related adverse reactions most frequently reported and leading to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. Approximately 3% of patients discontinued treatment due to an adverse reaction related to the drug.

Additional adverse reactions reported during post-marketing experience are included in the table under the category "Frequency not known", as frequency cannot be estimated from the available data.

The following adverse reactions have been observed and reported during treatment with linezolid with the following frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

• See section Warnings and special precautions for use

** See section Contraindications and Interaction with other medicinal products and other forms of interaction

Frequency of ADRs (adverse drug reactions) estimated using "The rule of three".

† See below

The following adverse reactions to linezolid were considered serious in rare cases: localized abdominal pain, transient ischaemic attacks, and hypertension.

† In controlled clinical trials where linezolid was administered for treatment periods of up to 28 days, anaemia was reported in 2% of patients. In a compassionate use programme involving patients with life-threatening infections and underlying comorbidities, the percentage of patients who developed anaemia when receiving linezolid ≤ 28 days was 2.5% (33/1326), compared with 12.3% (53/430) when treated for > 28 days. The proportion of reported cases of severe drug-related anaemia requiring blood transfusion was 9% (3/33) in patients treated ≤ 28 days and 15% (8/53) in those treated for more than 28 days.

Paediatric population

Safety data from clinical trials based on more than 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.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after authorisation of the medicinal product. This allows continued monitoring of the benefit-risk balance of the product. Healthcare professionals are encouraged to report suspected adverse reactions via the Spanish Pharmacovigilance System for Human Medicinal Products https://www.notificaram.es.

Overdose

No specific antidotes are known.

Cases of overdose have not been reported. However, the following information may be useful:

Supportive measures are recommended, maintaining glomerular filtration. Approximately 30% of the dose of linezolid is removed during 3 hours of haemodialysis, although data on removal of linezolid by peritoneal dialysis or haemoperfusion are not available.

Instructions for use and handling

For single use only.

Freeflex bag: Remove the outer wrapper only immediately before use, checking for minor leaks by firmly squeezing the bag. If leakage is detected, the bag must not be used, as sterility may have been compromised. The solution should be inspected visually before use, and only clear solutions free from particles should be used. Do not use these bags in series connections. Any unused solution must be discarded. Partially used bags must not be reconnected.

KabiPac vial:

Remove the vial from the outer packaging only immediately before use. The solution should be inspected visually before use, and only clear solutions free from particles should be used. Do not use these vials in series connections. Any unused solution must be discarded. No special requirements for disposal are needed. Any unused solution must be discarded in accordance with local requirements. Partially used vials must not be reconnected.

Linezolid Kabi 2 mg/ml solution for infusion is compatible with the following solutions:

• glucose 50 mg/ml (5%) for intravenous infusion,
• sodium chloride 0.9% for intravenous infusion,
• Ringer lactate solution for injectable preparations (Hartmann's solution for infusion).

Incompatibilities

No additives should be introduced into this solution. If linezolid is administered simultaneously with other drugs, each should be administered separately according to its instructions for use. Similarly, if the same intravenous line is used for sequential intravenous infusion of several drugs, it must be flushed before and after administration of linezolid with a compatible solution.

Linezolid Kabi solution for infusion 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 sodium ceftriaxone.

Shelf life

Physical and chemical stability in use has been demonstrated for 24 hours at 2-8°C and 25°C.

From a microbiological standpoint, the product should be used immediately unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination.

If not used immediately, the storage times and conditions prior to use are the responsibility of the user.

Special storage precautions

Freeflex bag: Store the bag in its original packaging to protect it from light until preparation.

KabiPac vial: Store the vial in its outer packaging until ready for use to protect it from light.