Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

Linezolid Demo 2 mg/ml, solution for infusion EFG

Read the entire leaflet carefully before you are given 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, pharmacist or nurse.
This medicine has been prescribed for you and should not be given to other people, even if they have the same symptoms as you, because it could harm them.
- If you experience any adverse reactions, consult your doctor, pharmacist or nurse, even if these are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet

What Linezolid Demo is and what it is used for
What you need to know before being treated with Linezolid Demo
How Linezolid Demo is administered
Possible side effects
How to store Linezolid Demo
Contents of the pack and other information

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

Linezolid is an antibiotic belonging to the oxazolidinone group that works by preventing the growth of certain bacteria (germs) that cause infections.

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

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

Do not store or reuse this medicine. If you have any leftover antibiotic after completing treatment, return it to the pharmacy for proper disposal. Medicines must not be disposed of via wastewater or household waste.

It is used to treat pneumonia and certain skin or subcutaneous tissue infections. Your doctor will have decided whether linezolid is appropriate for treating your infection.

2. What you need to know before being treated with Linezolid Demo

Do not take Linezolid Demo if:

You are allergic to linezolid or to any of the other ingredients of this medicine (listed in section 6).
You are taking or have taken within the last 2 weeks any medicines known as monoamine oxidase inhibitors (MAOIs, such as phenelzine, isocarboxazide, selegiline, moclobemida). These medicines are usually used to treat depression or Parkinson's disease.
You are breastfeeding. This medicine passes into breast milk and could affect the baby.

Warnings and precautions

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

Linezolid may not be suitable for you if you answer yes to any of the following questions. In such cases, inform your doctor, as they may need to monitor your general health and blood pressure before and during treatment, or may decide that another treatment is 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, whether or not you are taking medication for it?
Have you been diagnosed with hyperactive thyroid?
Do you have a tumor of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumors in the hormonal system, presenting symptoms such as diarrhea, skin flushing, wheezing)?
Do you suffer from manic depression, schizoaffective disorder, 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 Demo may lead to serotonin syndrome, a potentially life-threatening condition (see section 2 “Other medicines and Linezolid Demo” and section 4).

Take special care with Linezolid Demo

Inform your doctor before using this medicine if:

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

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

Vision problems such as blurred vision, changes in color vision, difficulty seeing clearly, or if you notice a reduction in your visual field.
Loss of sensation in your arms or legs, or a tingling or burning sensation in your arms or legs.
Diarrhea may occur while taking or after taking antibiotics, including linezolid. If diarrhea becomes severe, persists for a long time, or if you notice blood or mucus in your stools, stop taking this medicine immediately and consult your doctor. In this case, do not take medicines that stop or reduce intestinal movements.
Nausea or repeated vomiting, abdominal pain, or hyperventilation.
Malaise and dizziness with muscle weakness, headache, confusion, and memory impairment, which may indicate hyponatremia (low sodium levels in the blood).

Linezolid Demo and other medicines

There is a risk that linezolid may interact with certain medicines and cause adverse effects such as changes in blood pressure, body temperature, or heart rate.

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

Tell your doctor if you are taking or have taken within the last 2 weeks the following medicines, as you must not use linezolid if you are still taking or have recently taken them (see section 2 “Do not use Linezolid Demo”).

Monoamine oxidase inhibitors (MAOIs, such as phenelzine, isocarboxazide, selegiline, moclobemida). These medicines are commonly used to treat Parkinson's disease.

Also inform your doctor if you are taking the following medicines. Your doctor may decide to treat you with linezolid, but will need to assess your general condition and blood pressure before and during treatment. In other cases, your doctor may decide that another treatment is better for you.

Cold decongestants containing pseudoephedrine or phenylpropanolamine.
Certain asthma medications such as salbutamol, terbutaline, fenoterol.
Certain antidepressants known as tricyclic antidepressants or SSRIs (selective serotonin reuptake inhibitors). There are many medicines in this group, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
Medicines used to treat migraines, such as sumatriptan or zolmitriptan.
Medicines used to treat sudden severe 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 used to treat anxiety disorders, such as buspirone.
Medicines that prevent blood clotting, such as warfarin.
An antibiotic called rifampicin.

Linezolid Demo with food, drinks, and alcohol

You may take linezolid before, during, or after meals.
Avoid eating excessive amounts of aged cheese, yeast extracts, soybean extracts (e.g., soy sauce), and alcoholic beverages, especially draught beer and wine. The reason is that linezolid may react with a substance called tyramine, which occurs naturally in some foods. This interaction may cause an increase in your blood pressure.
If you experience headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility

The effect of linezolid in pregnant women is unknown. Therefore, pregnant women should not use linezolid unless advised by their doctor. If you are pregnant or breastfeeding, think you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before using this medicine.

You should not breastfeed while taking linezolid, as this medicine passes into breast milk and could affect your baby.

Driving and using machines

Linezolid 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 Demo contains glucose and sodium

Linezolid Demo solution contains 13.7 g of glucose per 300 ml dose, which should be taken into account in patients with diabetes mellitus.

This medicine contains 114 mg of sodium (a main component of table/cooking salt) in each 300 ml dose. This corresponds to 5.7% of the maximum daily sodium intake recommended for an adult.

3. How Linezolid Demo is administered

Adults

Follow exactly the instructions for using this medicine as described in this leaflet or as directed by your doctor, pharmacist, or nurse. If in doubt, consult your doctor, pharmacist, or nurse.

This medicine will be administered to you by a doctor or other healthcare professional as an intravenous infusion (a drip into a vein). The recommended dose for adults (18 years of age and older) is 300 ml (600 mg of linezolid) given twice daily directly into the bloodstream (intravenously) as an infusion over a period of 30 to 120 minutes.

If you are on a dialysis programme, linezolid will be administered after each dialysis session.

The usual duration of treatment is 10–14 days, but may be extended 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 the duration of your treatment.

While you are being treated with linezolid, your doctor will perform periodic blood tests to monitor your blood count.

If you are treated with linezolid for more than 28 days, your doctor should monitor your vision.

Use in children and adolescents

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

If you are given more Linezolid Demo than you should

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

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

If you forget to use Linezolid Demo

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Immediately inform your doctor, pharmacist, or nurse if you notice any of the following adverse effects while being treated with linezolid:

The more serious adverse effects of Linezolid Demo (with frequency stated in parentheses) 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 may need to be stopped. Skin reactions such as a raised purple rash due to inflammation of blood vessels (rare), red, sore, scaly skin (dermatitis) (uncommon), skin rash (common), itching (common).
Vision problems (uncommon), such as blurred vision (uncommon), changes in color vision (frequency not known), difficulty seeing clearly (frequency not known), or noticing a reduction in your field of vision (rare).
Severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis including pseudomembranous colitis), which in very rare instances may lead to complications that could become life-threatening (uncommon).
Repeated nausea or vomiting, abdominal pain, or rapid breathing (rare).
Seizures or convulsions have been reported (uncommon) in patients receiving linezolid treatment.
Serotonin syndrome (frequency not known): you should tell your doctor if you experience agitation, confusion, delirium, rigidity, tremor, lack of coordination, convulsions, rapid heartbeat, severe breathing problems, or diarrhoea (suggestive of serotonin syndrome) while also being treated with antidepressants called SSRIs or opioids (see section 2).
Unexplained bleeding or bruising, which may be due to a disturbance in the number of certain blood cells that can affect blood clotting or cause anaemia (common).
Reduction in the number of blood cells that can affect the ability to fight infections (uncommon). Some signs of infection include: fever (common), sore throat (uncommon), mouth ulcers (uncommon), and fatigue (uncommon).
Inflammation of the pancreas (uncommon).
Convulsions (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).

Cases of numbness, tingling, or blurred vision have been reported in patients who have taken linezolid 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 in the vagina or mouth
Headache
Metallic taste
Diarrhoea, nausea, or vomiting
Changes in certain blood test results, including those measuring proteins, salts, or enzymes used to assess liver or kidney function, or blood sugar levels
Difficulty sleeping
Increased blood pressure
Anaemia (low red blood cell levels)
Dizziness
Localized or generalized abdominal pain
Constipation
Indigestion
Localized pain
Reduction in platelet count

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

Inflammation of the vagina or female genital area
Tingling or numbness sensation
Swelling, discomfort, changes in tongue color
Dry mouth
Pain at or around the injection site (site of administration)
Inflammation of veins (including at the site where the intravenous line is placed for infusion)
Need to urinate more frequently
Chills
Feeling of thirst
Increased sweating
Hyponatraemia (low sodium levels in blood)
Kidney failure
Abdominal swelling
Pain at injection site
Increased creatinine
Stomach pain
Changes in heart rate (e.g., increased heart rate)
Decrease in blood cell counts
Weakness and/or sensory changes

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

Change in tooth surface color, which resolves with professional dental cleaning procedures

The following adverse effects have also been reported.

Frequency not known (frequency cannot be estimated from available data):

Alopecia (hair loss)

Reporting of adverse effects

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

5. Storage of Linezolid Demo

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

Do not use this medicine after the expiry date stated on the label and carton after "EXP". The expiry date refers to the last day of that month.

No special storage conditions are required.

Keep the bottle in the outer packaging to protect it from light.

After opening: from a microbiological standpoint, unless the opening method excludes the risk of bacterial contamination, the product should be used immediately. Otherwise, the storage times and conditions will be the responsibility of the user.

Do not use if visible particles are present in the solution or if the solution is not clear.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. These measures will help protect the environment.

6. Contents of the pack and other information

What Linezolid Demo contains

The active substance is linezolid. Each ml of solution contains 2 mg of linezolid. Each 300 ml infusion bottle contains 600 mg of linezolid.
The other components are monohydrate glucose (a type of sugar, see section 2), sodium citrate (E331, see section 2), citric acid monohydrate, hydrochloric acid (5N) (E507) or sodium hydroxide (5N) (E524), and water for injections.

What Linezolid Demo looks like and contents of the pack

Linezolid Demo is a clear, colourless to yellow solution for infusion.

It is presented in cardboard boxes containing 300 ml polypropylene bottles.

Pack sizes of 1, 2, 5, 10, 20 or 25 bottles are available.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Demo S.A., Pharmaceutical Industry
21st km National Road Athens-Lamia,
14568 Krioneri, Attiki,
Greece

Further information on this medicinal product can be obtained from the local representative of the Marketing Authorization Holder:

Local representative:
Kern Pharma, S.L.
Venus, 72 - Pol. Ind. Colón II
08228 Terrassa - Barcelona
Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Portugal:	Linezolid Demo
Greece:	ZETALID 2 mg/ml Solution for infusion
Spain:	Linezolid Demo 2 mg/ml solution for perfusion
Germany:	Linezolid Demo 2 mg/ml infusion solution

Date of the most recent review of this summary of product characteristics: June 2024

Detailed information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended for healthcare professionals only.

LinezolidDemo2 mg/ml solution for infusion EFG

IMPORTANT:

Consult the Summary of Product Characteristics (technical data sheet) before prescribing.

Linezolid is not active against infections caused by Gram-negative pathogenic microorganisms. Concomitant treatment against Gram-negative microorganisms should be initiated if co-infection with Gram-negative pathogenic microorganisms is confirmed or suspected.

Description

Single-use ready-to-use plastic bottles made of polypropylene, with molded plastic cap, rubber closure (type II), easy-open ring, or plastic closure caps with embedded elastomers (dual port). The bottle contains 300 ml of solution and is supplied in a carton. Each carton contains 1 bottle.

Single-use ready-to-use plastic bottles made of polypropylene, with molded plastic cap, rubber closure (type II), easy-open ring, or plastic closure caps with embedded elastomers (dual port).

Each bottle is contained within a metallized plastic overwrap. The bottle contains 300 ml of solution and is supplied in a carton. Each carton contains 2, 5, 10, 20 or 25 bottles.

The 300 ml bottle is available in pack sizes of 1, 2, 5, 10, 20 and 25 bottles.

Not all pack sizes may be marketed.

LinezolidDemo is a clear, colourless to yellow solution for infusion. Other components are: monohydrate glucose, sodium citrate (E331), monohydrate citric acid, hydrochloric acid (5N) (E507) or sodium hydroxide (5N) (E524), and water for injections.

Posology and method of administration

Linezolid must only be initiated in a hospital setting and after assessment by a specialist physician, 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 twice daily.

Recommended duration and dosing for adults:

The duration of treatment depends on the causative microorganism, the site of infection, severity, and the patient's clinical response.

The treatment duration recommendations indicated below reflect those used in clinical trials. For certain types of infection, shorter treatment courses may be appropriate, although this has not been evaluated in clinical trials.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid have not been established when administered for periods exceeding 28 days.

Infections associated with concurrent bacteraemia do not require an increase in the recommended dose or duration of treatment. The recommended doses for the infusion solution are as follows:

Infections	Dosage and route of administration twice daily	Duration of treatment
Hospital-acquired pneumonia	600 mg twice daily	10-14 consecutive days
Community-acquired pneumonia
Complicated skin and soft tissue infections	600 mg twice daily

Pediatric 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 adjustment is required.

Renal impairment: no dose adjustment is required.

Severe renal impairment (i.e., CrCl < 30 mL/min): no dose adjustment is required. Since the clinical relevance of exposure to high concentrations (up to 10 times) of the two main metabolites of linezolid in these patients is unknown, this medicinal product should be used with special caution in patients with severe renal dysfunction and administered only if the expected benefit outweighs the potential risk.

As approximately 30% of a dose of linezolid is removed during 3 hours of hemodialysis, linezolid should be administered after dialysis in patients undergoing this treatment. The main metabolites of linezolid are partially removed by hemodialysis, but their concentrations are 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 administered only if the expected benefit outweighs the potential risk.

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

Continue applying the same changes as in the summary of product characteristics.

Hepatic impairment: patients with mild to moderate hepatic impairment (Child-Pugh class A or B): no dose adjustment is required.

Severe hepatic impairment (Child-Pugh class C): as linezolid is metabolized via a non-enzymatic process, it is expected that impaired hepatic function will not significantly alter its metabolism, and therefore dose adjustment is not recommended. However, sufficient clinical data are lacking, and it is recommended that linezolid be used in these patients only if the expected benefit outweighs the theoretical risk.

Contraindications

Hypersensitivity to linezolid or to any of the excipients.

Linezolid must not be used in patients receiving medications that inhibit monoamine oxidase A or B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), nor during the two weeks following discontinuation of such medications.

Unless adequate means are available for close monitoring and blood pressure control, linezolid must not be administered to patients with the following baseline conditions or receiving the following medications:

Patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, affective disorders, or acute confusional state.
Patients receiving any of the following medications: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, and phenylpropanolamine), vasoconstrictors (e.g., adrenaline/epinephrine, noradrenaline/norepinephrine), dopaminergic drugs (e.g., dopamine, dobutamine), meperidine, or buspirone.

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

Special warnings and precautions for use

Marrow suppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in patients treated with linezolid. In patients who were monitored, hematological parameters returned toward pre-treatment levels after discontinuation of therapy. The risk of these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid may be at increased risk of hematological disorders 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 complete blood count is recommended in patients who: have pre-existing anemia, granulocytopenia, or thrombocytopenia; are receiving concomitant medications that may reduce hemoglobin levels, decrease blood cell counts, or adversely affect platelet count or function; have severe renal impairment or moderate to severe hepatic impairment; or are receiving more than 10–14 days of treatment. Linezolid should be administered to these patients only if close monitoring of hemoglobin levels, blood cell counts, and platelet counts is possible.

If significant myelosuppression occurs during treatment with linezolid, therapy should be discontinued unless continuation is considered absolutely necessary; in such cases, hematological parameters should be closely monitored and appropriate therapeutic measures implemented.

A complete blood count (including hemoglobin, platelets, absolute leukocyte count, and differential) should also be performed weekly in all patients receiving linezolid, regardless of baseline values.

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

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

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

In an open-label study in critically ill patients with catheter-related vascular infections, an excess of 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 status caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58–1.59), but it was significantly higher (p = 0.0162) in the linezolid group for patients infected with other microorganisms 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 group, more patients acquired infections due to Gram-negative microorganisms and died from infections caused by Gram-negative microorganisms or 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 alternative treatments are available. In such cases, concomitant therapy against Gram-negative microorganisms should be initiated.

Diarrhea and antibiotic-associated colitis

Cases of antibiotic-associated diarrhea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea 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, anemia, 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 4.3 of the summary of product characteristics). Therefore, concomitant administration of linezolid and serotonergic agents is contraindicated unless the administration of linezolid and serotonergic agents is absolutely necessary (see section 4.3 of the summary of product characteristics). 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.

Hyponatremia and SIADH

Hyponatremia 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 hyponatremia, 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, have been reported in patients treated with linezolid, 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 disturbance, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defects. In such cases, visual function should be evaluated as soon as possible and ophthalmologic consultation sought if necessary. Visual function should be monitored regularly in any patient treated with linezolid for longer than the recommended 28 days.

Continuation of linezolid treatment 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 seizures or risk factors for seizures was reported. Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI); however, it has no antidepressant effect at doses used for antibacterial treatment. Data from pharmacological interaction and safety studies of linezolid in patients receiving concomitant medications that increase this risk are very limited. Therefore, linezolid should not be used 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 (see section 4.5).

Superinfection

The effects of linezolid treatment on normal flora have not been evaluated in clinical trials. Occasionally, antibiotic use may lead to overgrowth of non-susceptible microorganisms. Approximately 3% of patients receiving recommended doses of linezolid 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 is considered to outweigh the potential risk.

Linezolid should be administered to patients with severe hepatic impairment only if the expected benefit is considered to outweigh 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 reduction 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, ischemic wounds, severe burns, or gangrene. Therefore, experience with the use of linezolid in the treatment of these conditions is limited.

Warnings about excipients

Glucose

This medicinal product contains 13.7 g of glucose in 300 mL, which should be taken into account in the management of patients with diabetes mellitus or other conditions associated with glucose intolerance.

Sodium

This medicinal product contains 114 mg of sodium per 300 mL dose, equivalent to 5.7% of the maximum daily intake of 2 g of sodium recommended by the WHO for an adult.

Linezolid Demo may be prepared for administration with solutions containing sodium (see section 6.6), and this should be considered in relation to the total sodium intake from all sources administered to the patient.

Interactions

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). Data on pharmacological interactions and safety of linezolid administered to patients receiving concomitant medications with risk of MAO inhibition are very limited. Therefore, linezolid should not be used in these circumstances unless close observation and monitoring of the patient are possible.

Potential interactions leading to increased blood pressure

Linezolid increased the hypertensive effect of pseudoephedrine and phenylpropanolamine hydrochloride in healthy normotensive volunteers. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride resulted in mean increases in systolic blood pressure of 30–40 mm Hg, compared with 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies have not been conducted in hypertensive patients. It is recommended that if linezolid is administered with vasoactive drugs (including dopaminergic agents), their doses 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 was reported of a patient experiencing symptoms similar to serotonin syndrome during concomitant use of linezolid and dextromethorphan, 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 (see section 4.3 of the summary of product characteristics). Therefore, since concomitant administration is contraindicated, the management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary is described in section 4.4 "Special warnings and precautions."

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 of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, CYP450-mediated pharmacokinetic 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 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 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 assess 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 must not be used during pregnancy unless clearly necessary, i.e., 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 interrupted before and during the entire course of 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

In the following table, all adverse reactions of this medicinal product and their frequencies are listed, based on all causality data from clinical trials involving more than 6,000 adult patients who received recommended doses of linezolid for up to a maximum of 28 days.

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

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

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).

Organ System Classification	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 (cannot be estimated from available data)
Infections and infestations	Candidiasis, oral candidiasis, vaginal candidiasis, fungal infections	Antibiotic-associated colitis, pseudomembranous colitis*, vaginitis
Blood and lymphatic system disorders	Thrombocytopenia, anemia†	Pancytopenia, leucopenia, neutropenia, eosinophilia		Sideroblastic anemia*	Myelosuppression*
Immune system disorders				Anaphylaxis
Metabolism and nutrition disorders		Hypotension		Lactic acidosis*
Psychiatric disorders	Insomnia
Nervous system disorders	Headache, taste disturbance (metallic taste), dizziness	Seizures, peripheral neuropathy, hypoesthesia, paresthesia			Serotonin syndrome**
Eye disorders		Optic neuropathy, blurred vision	Abnormal visual field changes*		Optic neuritis, vision loss, changes in visual acuity, changes in color vision
Ear and labyrinth disorders		Tinnitus
Cardiac disorders		Arrhythmia (tachycardia)
Vascular disorders	Hypertension	Transient ischemic attacks, phlebitis, thrombophlebitis
Gastrointestinal disorders	Diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia	Pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, soft stools, stomatitis, tongue disorders or color changes	Discoloration of dental surface
Hepatobiliary disorders	Abnormal liver function tests; increased AST, ALT, and alkaline phosphatase	Increased total bilirubin
Skin and subcutaneous tissue disorders	Pruritus, rash	Angioedema, urticaria, bullous dermatitis, dermatitis, diaphoresis	Toxic epidermal necrolysis#, Stevens-Johnson syndrome#, hypersensitivity vasculitis		Alopecia
Renal and urinary disorders	Increase in BUN	Renal failure, increase in creatinine, polyuria
Reproductive system and breast disorders		Vulvovaginal disorders
General disorders and administration site conditions	Fever, localized pain	Chills, fatigue, injection site pain, increased thirst
Investigations	Biochemistry Increased LDH, creatine kinase, lipase, amylase, or non-fasting glucose; decreased total proteins, albumin, sodium, or calcium; increased or decreased potassium or bicarbonate. Hematology Neutrophilia or eosinophilia, decreased hemoglobin, hematocrit, or erythrocyte count; increased or decreased platelet or leukocyte count	Biochemistry Increased sodium or calcium, decreased non-fasting glucose, increased or decreased chloride. Hematology Increased reticulocyte count, neutropenia

*See section 4.4

**See sections 4.3 and 4.5

Frequency of ADRs (adverse drug reactions) estimated using the "Rule of Three".

†See below

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

† In controlled clinical trials in which linezolid was administered for treatment periods of up to 28 days, 2.0% of patients reported anemia. In a compassionate use program for patients with life-threatening infections and underlying comorbidities, the percentage of patients who developed anemia when receiving linezolid for ≤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 anemia 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.

Overdose

No specific antidote is known.

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

Supportive measures should be initiated along with maintenance of glomerular filtration. Approximately 30% of the dose of linezolid is removed during 3 hours of haemodialysis, but data on removal of linezolid by peritoneal dialysis or haemoperfusion are not available.

Instructions for use and handling

For single use only.

Linezolid Demo infusion solution should be used immediately after piercing the rubber stopper to avoid any bacterial contamination. Protection from light during infusion is not required.

Do not use if any visible particles are present or if the solution is cloudy. Unused medicine or waste material must be disposed of in accordance with local regulations.

Linezolid Demo infusion solution is compatible with the following solutions: 5% glucose for intravenous infusion, 0.9% sodium chloride for intravenous infusion, lactated Ringer's solution for injectable preparations (Hartmann's solution).

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 own instructions for use. Similarly, if the same intravenous line is used for sequential intravenous infusion of several drugs, it should be flushed before and after administration of linezolid with a compatible solution.

Linezolid 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

Before opening: 3 years.

After opening: From a microbiological standpoint, unless the method of opening excludes the risk of bacterial contamination, the product should be used immediately; otherwise, storage times and conditions are the responsibility of the user.

Special precautions for storage

This medicinal product requires no special storage conditions.

Keep the vial in the outer packaging to protect from light.

Linezolid Demo 2 mg/ml solution for infusion EFG