LINEZOLID NORMON 2 mg/ml SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Linezolid Normon 2 mg/ml Solution for Infusion EFG

Linezolid

Read all of this leaflet carefully before you start using 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.

• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is not listed in this leaflet. See section 4.

Contents of the pack

1. What is Linezolid Normon 2 mg/ml solution for infusion EFG and what it is used for
2. What you need to know before you start using Linezolid Normon 2 mg/ml solution for infusion EFG
3. How to use Linezolid Normon 2 mg/ml solution for infusion EFG
4. Possible side effects
5. Storage of Linezolid Normon 2 mg/ml solution for infusion EFG

1. Contents of the pack and other information

1. What is Linezolid Normon 2 mg/ml solution for infusion EFG and what it is used for

Linezolid Normon 2 mg/ml 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 do not work for viral infections such as the flu or the common cold.

It is essential that you follow the instructions regarding the dose, intake, and duration of treatment indicated by your doctor.

Do not store or reuse this medication. If you have any leftover antibiotic after finishing the treatment, return it to the pharmacy for proper disposal. Do not throw away medications down the drain or in the trash.

It is used for the treatment of 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 start using Linezolid Normon 2 mg/ml solution for infusion EFG

Do not use Linezolid Normon 2 mg/ml 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 called 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. Linezolid Normon 2 mg/ml passes into breast milk and could affect your baby.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Linezolid Normon 2 mg/ml.

Linezolid Normon 2 mg/ml may not be suitable for you if you answer yesto any of the following questions. In that case, inform your doctor, as he/she will need to monitor your general health and blood pressure before and during treatment or may decide that another treatment is better for you.

Ask your doctor if you are not sure if any of these categories apply to your case.

• Do you have high blood pressure, whether or not you are taking medications to treat 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 bipolar disorder, schizophrenic disorder, 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 may cause serotonin syndrome, a potentially life-threatening condition (see sections 2 and 4).

Be especially careful with Linezolid Normon 2 mg/ml:

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 or tingling 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 stools contain blood or mucus, you should stop taking Linezolid Normon 2 mg/ml 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 rapid breathing.
• Discomfort and dizziness with muscle weakness, headache, confusion, and memory impairment that may indicate hyponatremia (low sodium levels in the blood).

Using Linezolid Normon 2 mg/ml with other medications

Occasionally, Linezolid Normon 2 mg/ml 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 must notuse Linezolid Normon 2 mg/ml if you are still taking them or have taken them recently (see also section 2, "Do not use Linezolid Normon 2 mg/ml"):

• 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 Normon 2 mg/ml, 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 remedies that contain pseudoephedrine or phenylpropanolamine.
• Certain medications for asthma, such as salbutamol, terbutaline, fenoterol.
• Certain antidepressants called tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many medications of this type, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, or sertraline.
• Medications used to treat migraines, such as sumatriptan or zolmitriptan.
• Medications used to treat 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 to severe pain.
• Medications used to treat anxiety disorders, such as buspirone.
• Medications that prevent blood clotting, such as warfarin.
• An antibiotic called rifampicin.

Using Linezolid Normon 2 mg/ml with food, drinks, and alcohol

• You can use Linezolid Normon 2 mg/ml before, during, or after meals.
• Avoid eating excessive amounts of cheese, yeast extracts, or soybean extracts (e.g., soy sauce) and alcoholic beverages, especially draft beer and wine. The reason is that Linezolid Normon 2 mg/ml 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 start experiencing headaches after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility

The effect of Linezolid Normon 2 mg/ml on pregnant women is unknown. Therefore, pregnant women should not use Linezolid Normon 2 mg/ml unless advised by their 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 medication.

You should not breastfeed while taking Linezolid Normon 2 mg/ml because this medication passes into breast milk and could affect your baby.

Driving and using machines

Linezolid Normon 2 mg/ml may cause dizziness or vision problems. If this happens, do not drive or use machines. Remember that if you are not feeling well, your ability to drive or use machines may be affected.

Linezolid Normon 2 mg/ml contains

Glucose

Patients with diabetes mellitus should note that this medication contains 13.7 g of glucose per dose.

Sodium

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

3. How to use Linezolid Normon 2 mg/ml solution for infusion EFG

Adults

Follow the administration instructions of the medication contained in this leaflet or as indicated by your doctor, pharmacist, or nurse. In case of doubt, 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, use Linezolid Normon 2 mg/ml after each session.

The normal duration of treatment is 10-14 days, but it may 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 using Linezolid Normon 2 mg/ml, your doctor will perform periodic blood tests to monitor your blood count.

If you take Linezolid Normon 2 mg/ml for more than 28 days, your doctor should monitor your vision.

Use in children and adolescents

Linezolid Normon 2 mg/ml is not normally used in children or adolescents (under 18 years).

If you use more Linezolid Normon 2 mg/ml than you should

If you think you may have been given more Linezolid Normon 2 mg/ml than you should, inform your doctor or nurse.

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 ingested.

If you forget to use Linezolid Normon 2 mg/ml

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

4. Possible side effects

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

The most serious side effects of Linezolid 2 mg/ml (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 Normon 2 mg/ml. Skin reactions such as a purple elevated 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 perception (unknown), difficulty seeing details (unknown), 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 epileptic seizures or convulsions (uncommon).
• 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).
• Unexplained bleeding or 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 loss of vision, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
• 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, vomiting, nausea.
• Alteration of some blood test results, including protein, salt, or enzyme tests that measure liver, kidney, or blood sugar function.
• Difficulty sleeping.
• Increased blood pressure.
• Anemia (reduction in the number of red blood cells).
• Itching.
• Dizziness.
• Abdominal pain, localized or generalized.
• Constipation.
• Indigestion.
• Localized pain.
• Decreased platelet count.

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

• Vaginal or genital inflammation in women.
• A sensation like tingling or numbness.
• 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 1000 people):

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

Also, the following side effects have been reported (unknown: frequency cannot be estimated from the available data):

• Alopecia (hair loss).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Linezolid Normon 2 mg/ml solution for infusion EFG

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

Do not use this medicine after the expiry date which is stated on the packaging after Exp. The expiry date is the last day of the month indicated.

Hospital staff will ensure that Linezolid 2 mg/ml solution for infusion is not used after the 'EXP' date printed on the bag and that it is administered immediately after breaking the seal. They will also visually inspect the solution before use and only use it if it is a clear and particle-free solution. They will also ensure that the solution is stored correctly in its box and packaging to protect it from light and keep it out of the sight and reach of children until use.

Special storage conditions:

Before opening:Do not store above 30°C. Do not refrigerate or freeze. Store in the original packaging (overbag and bag) to protect from light until ready for use.

After first opening:Linezolid Normon 2 mg/ml is physically and chemically stable for at least four hours at room temperature after first opening. From a microbiological point of view, unless the opening method excludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, the storage time and conditions are the responsibility of the user.

For single use only. Discard any remaining solution.

Do not use this medicine if you notice any particles or if the solution is not clear.

Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Container Content and Additional Information

Composition of Linezolid Normon 2 mg/ml

The active ingredient is linezolid. Each ml of solution contains 2 mg of linezolid. Each 300 ml bag contains 600 mg of linezolid.

The other components are glucose monohydrate (a type of sugar, see section 2 "Linezolid Normon 2 mg/ml contains glucose"), sodium citrate (E331, see section 2 "Linezolid Normon 2 mg/ml contains sodium"), citric acid (E330), hydrochloric acid diluted, 1N (E507), sodium hydroxide, 1N (E524), and water for injectable preparations.

Product Appearance and Container Content

Linezolid Normon 2 mg/ml is a transparent solution presented in individual perfusion bags containing 300 ml of solution. It is presented in packs of 10 bags.

Marketing Authorization Holder and Manufacturer

LABORATORIOS NORMON, S.A.

Ronda de Valdecarrizo, 6 – 28760 Tres Cantos – Madrid (SPAIN)

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

Spain: Linezolid Normon 2 mg/ml solution for infusion EFG

Portugal: Linezolida Normon

Date of the last revision of this leaflet:February 2023

Detailed and updated 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/

The following information is intended only for healthcare professionals:

Linezolid Normon 2 mg/ml solution for infusion EFG

Linezolid

IMPORTANT: Consult the technical 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

It is presented in cardboard boxes containing an overbag with a polyolefin bag with the infusion solution inside.

Linezolid Normon 2 mg/ml is available in containers containing 10 bags of 300 ml of infusion solution.

Linezolid Normon 2 mg/ml infusion solution contains linezolid 2mg/ml in a transparent solution. Other components are: glucose monohydrate (a type of sugar), sodium citrate (E331), anhydrous citric acid (E330), hydrochloric acid diluted 1N (E507), sodium hydroxide 1N (E524), and water for injectable preparations.

Posology and Method of Administration

Treatment with 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 the oral formulation when clinically indicated. In this case, no dose adjustment is required, as the oral bioavailability of linezolid is approximately 100%.

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

The recommended dose of linezolid should be administered intravenously (I.V.) twice a day.

Duration and Recommended Dosage for Treatment in 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 (see section 4.4).

Infections associated with bacteremia do not require increasing the recommended dose or duration of treatment.

The recommended doses are identical for the infusion solution and tablets and are as follows:

Pediatric Population:The safety and efficacy of linezolid have not been established in children under 18 years of age. 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 in these patients. Since the clinical relevance of exposure to high concentrations (up to 10 times) of the two main metabolites of linezolid is unknown, this medicinal product should be used with special caution in patients with severe renal insufficiency and should only be administered if the expected benefit outweighs the potential risk.

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 insufficiency. 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 undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal insufficiency (other than hemodialysis).

Hepatic Insufficiency:

Patient with mild to moderate hepatic insufficiency (Class A or B in the Child-Pugh scale): No dose adjustment is required.

Mild to Moderate Hepatic Insufficiency (Class C in the Child-Pugh scale):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 not enough 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 included in section 6.1.

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 two weeks following the administration of such medication.

Unless the necessary means are available to perform close monitoring and control of 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 (see section 4.4), tricyclic antidepressants, 5-HT1 receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, and phenylpropanolamine), vasopressors (e.g., epinephrine, norepinephrine), dopaminergic drugs (e.g., dopamine, dobutamine), pethidine, or buspirone.

Animal studies suggest that linezolid and its metabolites may pass into breast milk, so breastfeeding should be interrupted before and during treatment (see section 4.6).

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 have a higher risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal insufficiency, with or without dialysis. Therefore, it is recommended to perform close monitoring of the blood count in patients who: have pre-existing anemia, granulocytopenia, or thrombocytopenia; are receiving concomitant medication that may decrease hemoglobin levels or hematocrit or affect platelet count or function; have severe renal insufficiency; or are receiving more than 10-14 days of treatment. Linezolid should only be administered to these patients if close monitoring of hemoglobin levels, blood count, and platelet count is possible.

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 required blood transfusions more frequently. 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 treatment with linezolid, 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%) versus 58/363 (16.0%)]. The main factor influencing the mortality rate was the baseline status of Gram-positive infection. 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 were 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, there were more patients who acquired Gram-negative infections during the study and 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 co-infection with Gram-negative microorganisms is suspected or confirmed, if no alternative treatments are available (see section 4.1). 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 fatal 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 level, 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 4.5 of the technical data sheet). Therefore, the concomitant administration of linezolid and serotonergic agents is contraindicated (see section 4.3 of the technical data sheet), unless the administration of linezolid and serotonergic agents is absolutely necessary. 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, it should be considered to discontinue 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 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 disturbance, such as changes in visual acuity, changes in color vision, blurred vision, or defects in the visual field. In such cases, it is recommended to evaluate visual function as soon as possible and consult an ophthalmologist if necessary. Visual function should be regularly monitored in any patient treated with Linezolid Normon 2 mg/ml for a period longer than the recommended 28 days.

Continuation of treatment with Linezolid Normon 2 mg/2 ml 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 and safety studies of linezolid in patients who receive linezolid and have underlying diseases and/or receive concomitant treatment with drugs that increase this risk. Therefore, it is not recommended to use linezolid in these circumstances, unless close observation and monitoring of the patient are possible (see sections 4.3 and 4.5).

Use with tyramine-rich foods

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

Superinfection

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

Occasionally, the use of antibiotics may 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, appropriate 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 potential risk (see sections 4.2 and 5.2 of the summary of product characteristics).

It is recommended that linezolid be administered to patients with severe hepatic insufficiency with caution.

and only if the expected benefit outweighs the possible risk (see sections 4.2 and 5.2).

Fertility effects

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 potential effects of linezolid on the human male reproductive system are unknown (see section 5.3).

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 glucose. If your doctor has indicated that you have an intolerance to certain sugars, consult with them before taking this medication.

Patients with diabetes mellitus should note that this medication contains 13.7 g of glucose per dose.

Sodium

This medication contains 114 mg of sodium (main component of table/cooking salt) per dose. This is equivalent to 5.7% of the maximum recommended daily intake for an adult. Linezolid Normon 2mg/ml solution for infusion 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.

Interaction with other medications and other forms of interaction

Monoamine oxidase inhibitors

Linezolid is a non-selective reversible inhibitor of monoamine oxidase (MAOI). Data from linezolid interaction and safety studies 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 patient control are performed (see sections 4.3 and 4.4).

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 mmHg, compared to the 11-15 mmHg produced by linezolid alone, the 14-18 mmHg produced by pseudoephedrine or phenylpropanolamine alone, and the 8-11 mmHg produced by the placebo. Similar studies have not been conducted in hypertensive patients. It is recommended that if linezolid is administered with vasopressor drugs (including dopaminergic agents), the doses of these should be carefully titrated to achieve the desired response.

Potential serotonergic interactions

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

During post-marketing experience: a case of a patient experiencing symptoms similar to those of the serotonergic syndrome during the use of linezolid and dextromethorphan was 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 (see section 4.3 of the technical sheet), the management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary is described in section 4.4.

Use with foods rich in tyramine

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 ingestion 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).

Medications that are metabolized through cytochrome P450

Linezolid is not detectably metabolized by the cytochrome P450 enzyme system (CYP) nor does it inhibit any of the human CYP isoforms that are clinically significant (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, CYP450-induced 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 were administered 600 mg of linezolid twice a day for 2.5 days, with and 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 INR AUC. 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 (see section 5.3). There is a potential risk in humans.

Linezolid should not be used during pregnancy, unless it is 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, so breastfeeding should be interrupted before and during treatment.

Fertility

In animal studies, linezolid caused a reduction in fertility (see section 5.3).

Effects on ability to drive and use machines

Patients should be warned that they may experience dizziness or visual disturbance symptoms (as described in sections 4.4 and 4.8) while receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occur.

Adverse reactions

In the following table, all adverse reactions of this medication and their frequencies are listed based on all 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 "Unknown frequency" category, as the 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>

• See section 4.4

** See sections 4.3 and 4.5

# Estimated frequency of adverse drug reactions (ADRs) 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% of patients reported anemia. In a compassionate use program of 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 reported cases of drug-related severe 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.

Pediatric population

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.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions to the medication after its authorization. This allows for continuous monitoring of the benefit-risk relationship of the medication. Healthcare professionals are invited to report suspected adverse reactions through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es.

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 maintaining 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. The two main metabolites of linezolid are also eliminated to some extent by hemodialysis.

Signs of toxicity in rats, after administration of 3,000 mg/kg/day of linezolid, were decreased activity and ataxia, while dogs treated with 2,000 mg/kg/day presented with vomiting and tremors.

Instructions for use and handling

For single use only. Remove the outer bag only at the time of use, checking for minor leaks by firmly squeezing the bag. If there are leaks, it should not be used because it may have lost sterility. The solution should be visually inspected before use and only transparent and particle-free solutions should be used. These bags should not be used in serial connections with other medications (see section 6.2). Any remaining solution should be discarded.

It does not have special requirements for disposal. The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Do not reuse used bags.

Linezolid Normon 2 mg/ml 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 Normon 2 mg/ml is not physically compatible with the following compounds: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and sulfamethoxazole/trimethoprim. Additionally, it is not chemically compatible with sodium ceftriaxone.

Shelf life

Before opening: 2 years.

After opening: Linezolid Normon 2 mg/ml is physically and chemically stable for at least four hours at room temperature after the first 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 storage precautions

Do not store above 30°C. Do not refrigerate or freeze. Store in the original packaging (outer bag and bag) to protect from light until ready for use.

For storage conditions after the first opening, see section 6.3.

For additional information, consult: LABORATORIOS NORMON, S.A. Ronda de Valdecarrizo, 6 – 28760 Tres Cantos – Madrid (SPAIN). Tel. 918 06 52 40