LINEZOLID DEMO 2 mg/ml SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Linezolid Demo 2 mg/ml, Solution for Infusion EFG

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.

• This medicine has been prescribed for you only. Do not pass it on to others, as it may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

1. What is Linezolid Demo and what is it used for
2. What you need to know before you are treated with Linezolid Demo
3. How Linezolid Demo is administered
4. Possible side effects
5. Storage of Linezolid Demo
6. Package Contents and Additional Information

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

Linezolid is an antibiotic of 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 the flu or the common cold.

It is essential that you follow the instructions regarding dosage, administration, and treatment duration as indicated by your doctor.

Do not store or reuse this medication. If you have any leftover antibiotic after completing treatment, return it to the pharmacy for proper disposal. Do not dispose of medications through the drain or in the trash.

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

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

Linezolid Demo should not be administered if:

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

Warnings and Precautions

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

Linezolid may not be suitable for you if you answer yesto any of the following questions. In that case, inform your doctor, as they will need to monitor your overall health and blood pressure before and during treatment or may decide that another treatment is better for you.

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

• Do you have high blood pressure, whether or not you are taking medications for it?
• Have you been diagnosed with hyperthyroidism?
• Do you have a tumor of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumors in the hormonal system that cause symptoms such as diarrhea, skin flushing, and wheezing)?
• Do you suffer from manic depression, schizoaffective disorder, mental confusion, or other mental problems?
• Do you have a history of hyponatremia (low sodium levels in the blood) or take medications that reduce sodium levels in the blood, such as certain diuretics like hydrochlorothiazide?
• Do you take opioids?

The use of certain medications, including antidepressants and opioids, along with Linezolid Demo, may cause serotonin syndrome, a potentially life-threatening condition (see section 2 "Other Medicines and Linezolid Demo" and section 4).

Be careful with Linezolid Demo

Inform your doctor before using this medication if:

• You are an elderly patient
• You bruise easily and bleed
• 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 the following occur during treatment:

• Vision problems such as blurred vision, changes in color vision, difficulty seeing clearly, or if you notice a reduction in your field of vision.
• Numbness or tingling in your arms or legs or a sensation of burning in your arms or legs.
• Diarrhea may occur while taking or after taking antibiotics, including linezolid. If diarrhea becomes severe, lasts a long time, or if you notice that your stool contains blood or mucus, you should stop taking this medication immediately and consult your doctor. In this situation, do not take medications that stop or reduce intestinal movements.
• Repeated nausea or vomiting, abdominal pain, or hyperventilation
• Discomfort and dizziness with muscle weakness, headache, confusion, and memory impairment that may indicate hyponatremia (low sodium levels in the blood).

Linezolid Demo and other medications

There is a risk that linezolid may interact with certain medications and produce adverse effects 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 medication.

Inform your doctor if you are taking or have taken in the last 2 weeksthe following medications, as you should not uselinezolidif you are still taking or have recently taken them (see section 2 "Do not use Linezolid Demo").

• Monoamine oxidase inhibitors (MAOIs, such as phenelzine, isocarboxazid, selegiline, moclobemide). These medications are usually used to treat Parkinson's disease.

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

• Cold remedies that contain pseudoephedrine or phenylpropanolamine.
• Certain medications for asthma, such as salbutamol, terbutaline, fenoterol.
• Certain antidepressants known as tricyclic antidepressants or SSRIs (selective serotonin reuptake inhibitors). There are many medications of this type, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• Medications used to treat migraines, such as sumatriptan or zolmitriptan.
• Medications for treating severe allergic reactions, such as adrenaline (epinephrine).
• Medications that increase blood pressure, such as noradrenaline (norepinephrine), dopamine, and dobutamine.
• Opioids (e.g., pethidine) used to treat moderate or severe pain.
• Medications used to treat anxiety disorders, such as buspirone.
• Medications that prevent blood clotting, such as warfarin.
• An antibiotic called rifampicin.

Linezolid Demo with food, drinks, and alcohol

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

Pregnancy, breastfeeding, and fertility

The effect of linezolid on 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 have a baby, ask your doctor or pharmacist for advice before using this medication.

You should not breastfeed while taking linezolid because this medication passes into breast milk and could affect your baby.

Driving and using machines

Linezolid may cause dizziness or vision problems. If this happens, do not drive or use machines. Remember that if you do not feel well, your ability to drive or use machines may be affected.

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

3. How Linezolid Demo is administered

Adults

Follow the administration instructions of the medication contained in this leaflet or as indicated by your doctor, pharmacist, or nurse. If you are unsure, ask your doctor, pharmacist, or nurse.

This medication will be administered by a doctor or other healthcare professional through a drip (by infusion into a vein). The recommended dose for adults (18 years or older) is 300 ml (600 mg of linezolid) twice a day, administered directly into the bloodstream (intravenously) through a drip over a period of 30 to 120 minutes.

If you are on a dialysis program, you will be given linezolid after each session.

The usual duration of treatment is 10-14 days, but it can be extended up to 28 days. The safety and efficacy of this medication have not been established for treatment periods longer than 28 days. Your doctor will decide the duration of your treatment.

While 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 will need to monitor your vision.

Use in children and adolescents

Linezolid is not normally used in children or adolescents (under 18 years).

If you are given more Linezolid Demo than you should

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

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medication and the amount administered.

If you miss a dose of Linezolid Demo

Since this medication is administered under close supervision, it is very unlikely that a dose will be missed. If you think a dose of treatment has been missed, inform your doctor or nurse immediately. You cannot be given a double dose to make up for missed doses.

4. Possible side effects

Like all medications, this medication can cause side effects, although not everyone gets them.

Inform your doctor, pharmacist, or nurse immediatelyif you notice any of the following side effects while being treated with linezolid:

The most serious side effects of Linezolid Demo (whose frequency is between parentheses) are:

• Severe skin reactions (uncommon), swelling, particularly around the face and neck (uncommon), wheezing, and/or difficulty breathing (rare). This may be a sign of an allergic reaction, and it may be necessary to interrupt treatment with linezolid. Skin reactions such as a purplish raised rash due to inflammation of blood vessels (rare), red, painful, and scaly skin (dermatitis) (uncommon), skin rash (frequent), itching (frequent).
• Vision problems (uncommon), such as blurred vision (uncommon), changes in color vision (not known), difficulty seeing clearly (not known), or if you notice a reduction in your field of vision (rare).
• Severe diarrhea that contains blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare circumstances may lead to life-threatening complications (uncommon).
• Repeated nausea or vomiting, abdominal pain, or rapid breathing (rare).
• There have been reports of seizures or convulsions (uncommon) in patients treated with linezolid.
• Serotonin syndrome (unknown) should indicate to your doctor if you experience agitation, confusion, delirium, rigidity, tremor, incoordination, convulsions, rapid heartbeat, severe respiratory problems, and diarrhea (suggestive of serotonin syndrome) while also being treated with antidepressants called SSRIs or opioids (see section 2).
• Bleeding or unexplained bruising, which may be due to an alteration in the number of certain blood cells that can affect blood clotting or cause anemia (frequent).
• Reduction in the number of blood cells that can affect the ability to fight infections (uncommon). Some signs of infection include: fever (frequent), sore throat (uncommon), mouth ulcers (uncommon), and fatigue (uncommon).
• Pancreatitis (uncommon).
• Convulsions (uncommon).
• Transient ischemic attacks (temporary alteration of blood flow to the brain that causes short-term symptoms such as vision loss, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
• Ringing in the ears (tinnitus) (uncommon).

There have been reports of numbness, tingling, or blurred vision in patients who have taken linezolid for more than 28 days. If you experience vision difficulties, consult your doctor as soon as possible.

Other side effects include:

Frequent(may affect up to 1 in 10 people):

• Fungal infections, especially in the vagina or mouth
• Headache
• Metallic taste
• Diarrhea, nausea, or vomiting
• Alteration of some blood test results, including those for protein, salt, or enzyme tests that measure liver, kidney, or blood sugar function
• Difficulty sleeping
• Increased blood pressure
• Anemia (low red blood cell count)
• Dizziness
• Abdominal pain, localized or generalized
• Constipation
• Indigestion
• Localized pain
• Reduced platelet count

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

• Vaginal or genital inflammation in women
• Numbness or tingling sensation
• Swelling, discomfort, color changes of the tongue
• Dry mouth
• Pain at the injection site (vein) or around it
• Venous inflammation (including the location where the infusion line is placed)
• Need to urinate more frequently
• Chills
• Feeling of thirst
• Increased sweating
• Hyponatremia (low sodium levels in the blood)
• Kidney failure
• Abdominal swelling

• Pain at the injection site
• Increased creatinine
• Stomach pain
• Changes in heart rhythm (e.g., increased heart rate)
• Decrease in blood cell count
• Weakness and/or sensory changes

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

• Change in tooth color, which disappears with professional dental cleaning procedures

The following side effects have also been reported.

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

• Alopecia (hair loss)

Reporting side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report them directly through the Spanish Medicines Monitoring System for human use: www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Linezolid Demo

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

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

No special storage conditions are required.

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

After opening: from a microbiological point of view, 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 useif there are visible particles in the solution or if it is not transparent.

Do not dispose of any medication through wastewater or household waste. Ask your pharmacist how to dispose of medications that are no longer needed. These measures will help protect the environment.

6. Container Contents and Additional Information

What it containsLinezolidDemo

• 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 glucose monohydrate (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 injectable preparations.

Appearance of the Product and Container Contents ofLinezolidDemo

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

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

They are presented in packs of 1, 2, 5, 10, 20, or 25 bottles.

Not all packs may be marketed.

Marketing Authorization Holder and Manufacturer

Demo S.A., Pharmaceutical Industry

21st km National Road Athens-Lamia,

14568 Krioneri, Attiki,

Greece

For further information on this medicinal product, please contact 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 ProductisAuthorized in the Member States of theEconomicEuropeanSpacewiththe Following Names:

Date of Last Revision of this Leaflet:June 2024

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

This information is intended only for healthcare professionals

LinezolidDemo2 mg/ml solution for infusion EFG

IMPORTANT:

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

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

Description

Single-use plastic bottles, ready to use, made of polypropylene, with a molded plastic cap, rubber gasket (type II), and easy-opening ring, or plastic closure capsules with embedded elastomers (double port). The bottle contains 300 ml of solution and is presented in a box. Each box contains 1 bottle.

Single-use plastic bottles, ready to use, made of polypropylene, with a molded plastic cap, rubber gasket (type II), and easy-opening ring, or plastic closure capsules with embedded elastomers (double port).

Each bottle is presented in a metalized plastic sleeve. The bottle contains 300 ml of solution and is presented in a box. Each box contains 2, 5, 10, 20, or 25 bottles.

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

Not all packs may be marketed.

• LinezolidDemois a clear, colorless to yellow solution for infusion. Other components are: glucose monohydrate, sodium citrate (E331), citric acid monohydrate, hydrochloric acid (5N) (E507) or sodium hydroxide (5N) (E524), and water for injectable preparations.

Posology and Method of Administration

Linezolid should only be initiated in the hospital setting and after evaluation by a specialist physician, such as a microbiologist or an infectious disease specialist.

Patients who initiate treatment with the parenteral formulation may switch to any of the oral formulations when clinically indicated. In this case, no dose adjustment is required, as the oral bioavailability of linezolid is approximately 100%.

The solution for infusion should be administered over a period of 30 to 120 minutes.

The recommended dose of linezolid should be administered intravenously twice a day.

Duration and Recommended Dosage for Adults:

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

The recommendations on the duration of treatment indicated below reflect those used in clinical trials. For some types of infection, it may be convenient to prescribe shorter treatments, although this has not been evaluated in clinical trials.

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

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

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 summary of product characteristics, but no posological recommendation can be made.

Elderly Patients:no dose adjustment is required.

Renal Insufficiency:no dose adjustment is required.

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

Since approximately 30% of the linezolid dose is eliminated during 3 hours of hemodialysis, linezolid should be administered after dialysis in patients receiving such treatment. The main metabolites of linezolid are partially eliminated 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 insufficiency undergoing dialysis and only if the expected benefit outweighs the potential risk.

So far, there is no experience with the administration of linezolid in patients on continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal impairment (other than hemodialysis).

Continue to apply the same changes as in the data sheet

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

Severe hepatic insufficiency (Child-Pugh class C): since linezolid is metabolized through a non-enzymatic process, it is expected that hepatic function impairment will not significantly alter its metabolism, and therefore, no dose adjustment is recommended. However, there are insufficient clinical data, and it is recommended to use linezolid in these patients only if the expected benefit outweighs the theoretical risk.

Contraindications

Hypersensitivity to linezolid or to any of the excipients.

Linezolid should not be used in patients who are taking monoamine oxidase inhibitors A or B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide) or during the 2 weeks following the administration of such medication.

Unless the necessary means are available to closely monitor and control blood pressure, linezolid should not be administered to patients with the following underlying clinical conditions or who are being treated with the following medications:

• Patient with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, psychoaffective disorders, or acute confusional state.

• Patient taking any of these medications: serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, and phenylpropanolamine), vasopressors (e.g., adrenaline/epinephrine, noradrenaline/norepinephrine), dopaminergic drugs (e.g., dopamine, dobutamine), pethidine, or buspirone.

Breast-feeding should be interrupted before and during treatment (see section 4.6 of the data sheet).

Special Warnings and Precautions for Use

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in patients treated with linezolid. In patients who were followed up, it has been seen that after discontinuing treatment, the affected hematological parameters have increased towards pre-treatment levels. The risk of these effects appears to be associated with the duration of treatment. Elderly patients treated with linezolid may be at higher risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal insufficiency, with or without dialysis, and in patients with moderate to severe hepatic insufficiency. Therefore, it is recommended to closely monitor the blood count in patients who: have pre-existing anemia, granulocytopenia, or thrombocytopenia; are receiving concomitant medication that may decrease hemoglobin levels, reduce the count, or adversely affect platelet count or function; have severe renal insufficiency or moderate to severe hepatic insufficiency; or are receiving more than 10-14 days of treatment. Linezolid should only be administered to these patients if it is possible to closely monitor hemoglobin levels, blood count, and platelet count.

If significant myelosuppression occurs during treatment with linezolid, treatment should be discontinued, unless continuation of treatment is considered absolutely necessary, in which case, close monitoring of hematological parameters should be performed, and appropriate therapeutic measures should be implemented.

Additionally, a complete blood count (including hemoglobin, platelets, absolute leukocyte count, and formula) is recommended weekly for patients receiving linezolid, regardless of their baseline blood count.

In compassionate use studies, a higher incidence of severe anemia was reported in patients being treated with linezolid for periods longer than the recommended maximum treatment duration of 28 days. These patients more frequently required blood transfusions. Cases of anemia requiring blood transfusion have also been reported during post-marketing experience, 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 the cases where the start time is known, most patients were treated for more than 28 days. Most patients recovered totally or partially after discontinuing linezolid treatment, with or without treatment for anemia.

Mortality Imbalance in a Clinical Trial in Patients with Gram-Positive Catheter-Related Vascular Infections

In an open study in severely 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 the mortality rate was the baseline status of infection 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 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 group, there were more patients who acquired Gram-negative infections during the study and who died from Gram-negative infections and polymicrobial infections. Therefore, linezolid should only be used in patients with complicated skin and soft tissue infections in whom a co-infection with Gram-negative microorganisms is suspected or confirmed, if no alternative treatments are available. In these circumstances, concomitant treatment against Gram-negative microorganisms should be initiated.

Antibiotic-Associated Diarrhea and Colitis

With the use of almost all antibiotics, including linezolid, cases of antibiotic-associated diarrhea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported, whose severity can range from mild diarrhea to life-threatening colitis. Therefore, it is essential 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, treatment with antibacterial agents, including linezolid, should be discontinued, and appropriate therapeutic measures should be implemented immediately. In this situation, medications that inhibit peristalsis are contraindicated.

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 being treated with linezolid, should receive immediate medical attention. If lactic acidosis occurs, the benefits of continuing treatment with linezolid should be weighed against the 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 the duration of treatment is longer than 28 days.

Serotonin Syndrome

Spontaneous reports of serotonin syndrome associated with the concomitant administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, have been communicated (see section 4.3 of the data sheet). 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 data sheet). In these cases, patients should be closely monitored for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and incoordination. If signs or symptoms appear, consideration should be given to discontinuing one or both agents; if treatment with the serotonergic agent is discontinued, symptoms may disappear.

Hyponatremia and SIADH

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients treated with linezolid. It is recommended to regularly monitor serum sodium levels in patients at risk of hyponatremia, such as elderly patients or patients taking medications that may reduce sodium levels in the blood (e.g., thiazide diuretics such as hydrochlorothiazide).

Optic and Peripheral Neuropathy

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

All patients should be warned to report symptoms of visual disturbances, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defects. In such cases, it is recommended to evaluate visual function as soon as possible and to consult an ophthalmologist if necessary. Visual function should be regularly monitored in any patient treated with linezolid for a period longer than the recommended 28 days.

Continuation of treatment with linezolid in patients who have suffered optic or peripheral neuropathy should be weighed against the potential risks.

There may be a higher risk of neuropathies when linezolid is used in patients who are currently taking or have recently taken 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 doctor if they have a history of seizures.

Monoamine Oxidase Inhibitors

Linezolid is a reversible and non-selective monoamine oxidase inhibitor (MAOI); however, it does not have any antidepressant effect at the doses used for antibacterial treatment. There are hardly any data from pharmacological interaction studies available

and safety of linezolid in patients receiving linezolid and presenting underlying pathologies and/or receiving concomitant treatment with drugs that increase this risk. Therefore, it is not recommended to use linezolid in these circumstances, unless it is possible to perform close observation and monitoring of the patient.

Use with tyramine-rich foods

Patients should be warned not to consume large amounts of tyramine-rich foods (see section 4.5).

Superinfection

The effects of treatment with linezolid on normal flora have not been evaluated in clinical trials. Occasionally, the use of antibiotics can produce the overgrowth of non-susceptible microorganisms. Approximately 3% of patients who received linezolid at the recommended doses during clinical trials presented treatment-associated candidiasis. In cases of superinfection during treatment, adequate measures should be taken.

Special populations

Linezolid should be used with special caution in patients with severe renal insufficiency, and only if the expected benefit is considered superior to the possible risk.

It is recommended that linezolid be administered to patients with severe hepatic insufficiency only if it is considered that the expected benefit outweighs the possible risk.

Effects on fertility

In studies conducted in adult male rats with linezolid exposure levels similar to those expected in humans, a reversible decrease in fertility and abnormal sperm morphology were observed. The possible 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, decubitus ulcers, ischemic lesions, severe burns, or gangrene. Consequently, there is limited experience with the use of linezolid in the treatment of these pathologies.

Warnings about excipients

Glucose

This medication contains 13.7 g of glucose in 300 ml, which should be taken into account in the treatment of patients with diabetes mellitus or other conditions associated with glucose intolerance.

Sodium

This medication 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 from all sources that will be administered to the patient.

Interactions

Monoamine oxidase inhibitors

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

Potential interactions that produce increased blood pressure

Linezolid increased the hypertensive effect produced by pseudoephedrine and phenylpropanolamine hydrochloride in healthy normotensive volunteers. The simultaneous administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride produced mean increases in systolic blood pressure of the order of 30-40 mm Hg, compared to the 11-15 mm Hg produced by linezolid alone, the 14-18 mm Hg produced by pseudoephedrine or phenylpropanolamine alone, and the 8-11 mm Hg produced by the placebo. Similar studies have not been conducted in hypertensive patients. It is recommended that if linezolid is administered with drugs with vasopressor effects (including dopaminergic agents), the doses of these should be carefully titrated to achieve the desired response.

Potential serotonergic interactions

In healthy volunteers, the potential pharmacological interaction of linezolid with dextromethorphan was studied. Two doses of 20 mg of dextromethorphan were administered with a difference of 4 hours, with or without linezolid. In healthy subjects who received linezolid and dextromethorphan, no effects of the serotonergic syndrome (confusion, delirium, restlessness, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

During post-marketing experience: a case of a patient who experienced symptoms similar to those of the serotonergic syndrome during the intake of linezolid and dextromethorphan has been reported, which resolved with the interruption of both treatments.

Cases of serotonergic syndrome have been reported during the clinical use of linezolid in combination with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids (see section 4.3 of the technical sheet). Therefore, since concomitant administration is contraindicated, the management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary is described in the "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 it is only necessary to avoid the intake of excessive amounts of foods or beverages with high tyramine content (e.g., mature cheese, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce).

Drugs that are metabolized through cytochrome P450

Linezolid is not detectably metabolized by the cytochrome P450 enzyme system nor does it inhibit any of the human isoforms of P450 that are clinically significant (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no pharmacological interactions induced by CYP450 with linezolid are expected.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid has been studied in sixteen healthy adult males who were administered 600 mg of linezolid twice a day for 2.5 days, with or without 600 mg of rifampicin once a day for 8 days. Rifampicin decreased the Cmax and AUC of linezolid by a mean of 21% [90% CI, 15, 27] and a mean of 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical relevance are unknown.

Warfarin

The simultaneous administration of warfarin and linezolid at steady state produced a reduction of 10% of the maximum mean INR (International Normalized Ratio) and a decrease of 5% of the AUC of the INR. The data from patients who have received 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 it is clearly necessary, i.e., only if the potential benefit outweighs the possible risk.

Breastfeeding

Animal data suggest that linezolid and its metabolites may pass into breast milk, so breastfeeding should be interrupted 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 warned that they may experience dizziness or visual disturbance symptoms while receiving linezolid, and they should be advised not to drive or use machinery if any of these symptoms occur.

Adverse reactions

The following table lists all the adverse reactions of this medication and their frequencies based on all the causality data from clinical trials in which more than 6,000 adult patients participated who received the 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 that led to treatment discontinuation were headache, diarrhea, nausea, and vomiting. About 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 in the "Frequency not known" category, as the frequency cannot be estimated from the available data.

The following adverse reactions to linezolid were reported with the following frequencies: Very common (≥ 1/10), common (≥ 1/100 to <1>

*See section 4.4

**See sections 4.3 and 4.5

# Estimated frequency of adverse drug reactions using "The rule of three".

† See below

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

† In controlled clinical trials in which linezolid was administered for periods of up to 28 days of treatment, 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 they received linezolid ≤ 28 days was 2.5% (33/1326) compared to 12.3% (53/430) when they were treated for > 28 days. The proportion of cases of severe anemia related to the medication that required blood transfusion was 9% (3/33) in patients treated ≤ 28 days and 15% (8/53) in those treated for more than 28 days.

Pediatric population

The safety data from clinical trials based on more than 500 pediatric patients (from birth to 17 years) do not indicate that the safety profile of linezolid for pediatric patients differs from that of adults.

Overdose

No specific antidote is known.

No cases of overdose have been reported. However, the following information may be useful:

Supportive measures should be instituted along with maintenance of glomerular filtration. Approximately 30% of the linezolid dose is eliminated during 3 hours of hemodialysis, but no data are available on the elimination of linezolid by peritoneal dialysis or hemoperfusion.

Instructions for use and handling

For single use only.

Linezolid Demo solution for infusion should be used immediately after piercing the rubber stopper with the aim of avoiding any bacterial contamination. It is not necessary to protect from light during infusion.

Do not use if there are any visible particles or if the solution is turbid. Unused medication or any remaining material should be disposed of in accordance with local regulations.

Linezolid Demo solution for infusion is compatible with the following solutions: 5% glucose for intravenous infusion,

0.9% sodium chloride for intravenous infusion, Ringer's lactate solution for injectable preparations (Hartmann's solution).

Incompatibilities

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

It is known that linezolid is not physically compatible with the following compounds: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, phenytoin sodium, and sulfamethoxazole/trimethoprim. Additionally, it is not chemically compatible with sodium ceftriaxone.

Shelf life

Before opening: 3 years.

After opening: From a microbiological point of view, 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.

Special precautions for storage

This medication does not require special storage conditions.

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