Linezolid Normon 2 mg/ml solution for infusion EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Linezolid Normon 2 mg/ml infusion solution EFG

Linezolid

Read the entire leaflet carefully before you start using 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, ask your doctor, pharmacist or nurse.

• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

2. What you need to know before using Linezolid Normon 2 mg/ml infusion solution EFG

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

4. Possible side effects

5. How to store Linezolid Normon 2 mg/ml infusion solution EFG

6. Contents of the pack and other information

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

Linezolid Normon 2 mg/ml is an antibiotic belonging to the oxazolidinone group, which 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 influenza or the common cold.

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

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

It is used to treat pneumonia and certain skin or soft tissue infections.

Your doctor will have determined whether linezolid is appropriate for treating your infection.

2. What you need to know before starting to use Linezolid Normon 2 mg/ml solution for infusion EFG

Do not use Linezolid Normon 2 mg/ml 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, isocarboxazid, selegiline, moclobemide). These medicines 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

Talk to 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 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 situations 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 (hyperthyroidism)?
• Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumours in the hormonal system, associated with symptoms such as diarrhoea, skin flushing, and wheezing)?
• Do you suffer from bipolar disorder, schizophrenia, mental confusion, or other mental health problems?
• Do you have a history of hyponatraemia (low sodium levels in the blood), or are you taking medicines that reduce sodium levels in the blood, such as certain diuretics like hydrochlorothiazide?
• Are you taking opioids?

Using certain medicines, including antidepressants and opioids, together with linezolid may cause serotonin syndrome, a potentially life-threatening condition (see section 2 and 4).

Take special care with Linezolid Normon 2 mg/ml:

Inform your doctor before using this medicine if:

• You are elderly.
• You bruise easily or bleed excessively.
• You have anaemia (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 diarrhoea.

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

• Vision problems such as blurred vision, changes in colour vision, difficulty seeing clearly, or 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.
• Diarrhoea may occur while taking or after taking antibiotics, including linezolid. If diarrhoea becomes severe, prolonged, or if you notice blood or mucus in your stools, stop taking Linezolid Normon 2 mg/ml immediately and consult your doctor. In this situation, do not take medicines that stop or reduce intestinal movements.
• Nausea or repeated vomiting, abdominal pain, or rapid breathing.
• Malaise and dizziness with muscle weakness, headache, confusion, and memory impairment, which may indicate hyponatraemia (low sodium levels in the blood).

Using Linezolid Normon 2 mg/ml with other medicines

Linezolid Normon 2 mg/ml may sometimes 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 medicines.

Inform your doctor if you are taking or have taken within the last 2 weeks the following medicines, as you must not use Linezolid Normon 2 mg/ml if you are still taking them or have recently taken them (see also section 2, "Do not use Linezolid Normon 2 mg/ml"):

• Monoamine oxidase inhibitors (MAOIs, such as phenelzine, isocarboxazid, selegiline, moclobemide). 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 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 more suitable for you.

• Decongestants for colds containing pseudoephedrine or phenylpropanolamine.
• Certain asthma medicines such as salbutamol, terbutaline, fenoterol.
• Certain antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many medicines in this group, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, or 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.

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

• You may use Linezolid Normon 2 mg/ml before, during, or after meals.
• Avoid eating excessive amounts of cheese, yeast extracts, or soybean seed extracts (e.g. soy sauce), and avoid alcoholic beverages, especially draught beer and wine. This is because Linezolid Normon 2 mg/ml may react with a substance called tyramine, naturally present in some foods. This interaction may cause an increase in your blood pressure.
• If you develop a headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility

The effect of Linezolid Normon 2 mg/ml in 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 medicine.

You should not breastfeed while taking Linezolid Normon 2 mg/ml, as this medicine 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 occurs, do not drive or operate machinery. Remember that if you do not feel well, your ability to drive or operate machinery may be impaired.

Linezolid Normon 2 mg/ml contains

Glucose

Patients with diabetes mellitus should be aware that this medicine contains 13.7 g of glucose per dose.

Sodium

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

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

Adults

Follow exactly the instructions for administering this medicine as stated 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 via intravenous infusion (drip into a vein). The recommended dose for adults (18 years of age or older) is 300 ml (600 mg of linezolid) twice daily, administered directly into the bloodstream (intravenously) as an infusion over a period of 30 to 120 minutes.

If you are on a dialysis regimen, use Linezolid Normon 2 mg/ml after each dialysis session.

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

While you are receiving Linezolid Normon 2 mg/ml, your doctor will perform periodic blood tests to monitor your blood cell counts.

If you receive Linezolid Normon 2 mg/ml for longer 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 and adolescents (under 18 years of age).

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 have, inform your doctor or nurse.

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at 91 562 04 20, specifying the medicine and the amount ingested.

If you forget to use Linezolid Normon 2 mg/ml

As 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 omitted, inform your doctor or nurse. Do not double the next dose to make up for a missed dose.

4. Possible adverse effects

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

The most serious adverse effects of Linezolid 2 mg/ml (frequency 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 Normon 2 mg/ml may need to be discontinued. Skin reactions such as 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 perception (frequency not known), difficulty seeing fine details (frequency not known), or if you notice a reduction in your visual field (rare).
• Severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis including pseudomembranous colitis), which in rare cases could lead to complications that may become life-threatening (uncommon).
• Nausea or repeated vomiting, abdominal pain, or rapid breathing (rare).
• Seizures or convulsions have been reported (uncommon).
• Serotonin syndrome (frequency not known): you must inform your doctor if you experience agitation, confusion, delirium, muscle rigidity, tremor, lack of coordination, convulsions, rapid heartbeat, severe breathing problems, or diarrhoea (suggestive of serotonin syndrome) while also being treated with antidepressants known as SSRIs or opioids (see section 2).
• Unexplained bleeding or bruising, which may be due to changes 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, vomiting, nausea.
• Abnormal blood test results, including tests for proteins, electrolytes, or enzymes measuring liver, kidney function, or blood sugar levels.
• Difficulty sleeping.
• Increased blood pressure.
• Anaemia (reduction in the number of red blood cells).
• Itching.
• Dizziness.
• Localised or generalised abdominal pain.
• Constipation.
• Indigestion.
• Localised 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 sensations.
• Swelling, discomfort, changes in tongue color.
• Dry mouth.
• Pain at the injection site (infusion site) or around it.
• Inflammation of veins (including at the site where the infusion line is placed).
• Need to urinate more frequently.
• Chills.
• Feeling thirsty.
• Increased sweating.
• Hyponatremia (low sodium levels in blood).
• Kidney failure.
• Abdominal swelling.
• Pain at injection site.
• Increased creatinine.
• Stomach pain.
• Changes in heart rate (e.g., increased heartbeat).
• Decrease in blood cell counts.
• Weakness and/or sensory changes.

Rare (may affect up to 1 in 1000 people):

• Change in the colour of tooth surface, which disappears 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 a possible 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 Normon 2 mg/ml infusion solution EFG

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

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

Hospital staff will ensure that Linezolid 2 mg/ml infusion solution is not used after the 'Exp' date printed on the bag and that it is administered immediately after breaking the seal. They will also inspect the solution visually before use and will use it only if it is a clear, particle-free solution. Furthermore, they will ensure that the solution is stored correctly in its original carton and packaging to protect it from light and from being accessed by children until the time of use.

Special storage conditions:

Before opening: Do not store above 30°C. Do not refrigerate or freeze. Store in the original packaging (overpouch 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 standpoint, unless the opening procedure excludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user.

For single use only. Any unused solution should be discarded.

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

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

6. Pack contents and other information

Composition of Linezolid Normon 2 mg/ml

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

The other components are monohydrate glucose (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), diluted hydrochloric acid, 1N (E507), sodium hydroxide, 1N (E524), and water for injections.

Appearance of the product and contents of the pack

Linezolid Normon 2 mg/ml is a clear solution supplied in individual infusion bags containing 300 ml of solution. It is available 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 most recent review of this summary: February 2023

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/

The following information is intended for healthcare professionals only:

Linezolid Normon 2 mg/ml solution for infusion EFG

Linezolid

IMPORTANT: Consult the Summary of Product Characteristics before prescribing.

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

Description

Presented in cardboard boxes containing an overpouch with a polyolefin bag containing the infusion solution inside.

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

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

Posology and method of administration

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

Patients starting treatment with the parenteral formulation may be switched to the oral formulation 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 (I.V.) twice daily.

Recommended duration and dosage for treatment in adults:

The duration of treatment depends on the microorganism involved, 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 durations 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 (see section 4.4).

Bacteraemia-associated infections do not require an increase in the recommended dose or duration of treatment.

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

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

Paediatric population: The safety and efficacy of linezolid in children under 18 years of age have not been established. The currently available data are described in sections 4.8, 5.1 and 5.2 of the summary of product characteristics; 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 in these patients. However, 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 medicine should be used with special caution in patients with severe renal impairment and only if the expected benefit outweighs the potential risk.

As approximately 30% of the dose of linezolid is removed during 3 hours of haemodialysis, linezolid should be administered after dialysis in patients undergoing this treatment. The main metabolites of linezolid are partially removed by haemodialysis, 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 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 renal impairment (other than haemodialysis).

Hepatic impairment:

Patients with mild to moderate hepatic impairment (Child-Pugh Class A or B): No dose adjustment is required.

Mild to moderate hepatic impairment (Child-Pugh Class C): As linezolid is metabolised via a non-enzymatic process, it is expected that impaired liver function will not significantly alter its metabolism and therefore dose adjustment is not recommended. However, sufficient clinical data are not available 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 listed in section 6.1.

Linezolid must not be used in patients receiving monoamine oxidase inhibitors (MAOIs) A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide), or during the two weeks following discontinuation of such medication.

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

• Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, affective disorders, or acute confusional state.
• Patients receiving any of the following medications: serotonin reuptake inhibitors (see section 4.4), tricyclic antidepressants, serotonin 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 indicate that linezolid and its metabolites may be excreted in breast milk; therefore, breastfeeding must be discontinued before and during treatment (see section 4.6).

Special warnings and precautions for use

Myelosuppression

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

If significant myelosuppression occurs during treatment with linezolid, treatment should be discontinued unless continuation is considered absolutely necessary, in which case haematological parameters should be closely monitored and appropriate therapeutic measures implemented.

In addition, a complete blood count (including haemoglobin, platelets, absolute white blood cell count and differential) should be performed weekly in all patients receiving linezolid, regardless of their baseline blood count.

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

Cases of sideroblastic anaemia have been reported during post-marketing experience. In cases where onset 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 anaemia.

Mortality imbalance in a clinical trial in patients with Gram-positive catheter-related vascular infections

In an open-label study in critically ill patients with catheter-related vascular infections, an excess 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 Gram-positive infection status. Mortality rates were similar in patients with infections caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58–1.59), but significantly higher (p = 0.0162) in the linezolid arm for patients infected with any other microorganism or in whom no baseline microorganism was isolated (odds ratio 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days of discontinuation of the study drug. In the linezolid arm, more patients acquired Gram-negative infections during the study and died from infections caused by Gram-negative microorganisms and polymicrobial infections. Therefore, linezolid should only be used in patients with complicated skin and soft tissue infections in whom co-infection with Gram-negative microorganisms is suspected or confirmed if no other alternative treatments are available (see section 4.1). In such circumstances, concomitant therapy against Gram-negative microorganisms should be initiated.

Diarrhoea and antibiotic-associated colitis

Cases of antibiotic-associated diarrhoea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhoea to fatal colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhoea during or after treatment with linezolid. If antibiotic-associated diarrhoea or colitis is suspected or confirmed, antibacterial agents, including linezolid, should be discontinued and appropriate therapeutic measures initiated immediately. In this situation, drugs 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 seek immediate medical attention. If lactic acidosis occurs, the benefits of continuing linezolid treatment 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, anaemia and neuropathy (optic and peripheral) may occur; these events are more frequent when treatment duration exceeds 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids (see section 4.5 of the product information), have been reported. Therefore, concomitant administration of linezolid and serotonergic agents is contraindicated (see section 4.3 of the product information), unless the administration of linezolid and serotonergic agents is absolutely necessary. In such cases, patients should be carefully observed for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperthermia, hyperreflexia and incoordination. If signs or symptoms occur, discontinuation of one or both agents should be considered; symptoms may resolve if treatment with the serotonergic agent is discontinued.

Hyponatraemia and SIADH

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

Optic and peripheral neuropathy

Cases of peripheral neuropathy, as well as optic neuropathy and optic neuritis, which occasionally 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 maximum recommended duration of 28 days.

All patients should be advised to report symptoms of visual disturbance, such as changes in visual acuity, changes in colour vision, blurred vision or visual field defects. In such cases, visual function should be evaluated as soon as possible and an ophthalmologist consulted if necessary. Visual function should be monitored regularly in any patient treated with Linezolid Normon 2 mg/ml for longer than the recommended 28 days.

Continuation of treatment with Linezolid Normon 2 mg/2 ml in patients who have experienced optic or peripheral neuropathy should be evaluated against the possible risks.

There may be an increased risk of neuropathies 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 the doses used for antibacterial treatment. Data on pharmacological interactions and safety of linezolid in patients receiving concomitant medications or with underlying conditions that increase this risk are very limited. Therefore, linezolid should not be used in such circumstances unless close observation and monitoring of the patient is possible (see sections 4.3 and 4.5).

Use with tyramine-rich foods

Patients should be advised not to consume large amounts 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, the use of antibiotics may lead to overgrowth of non-susceptible microorganisms. Approximately 3% of patients receiving linezolid at the recommended doses in clinical trials developed treatment-associated candidiasis. In cases of superinfection during treatment, appropriate measures should be taken.

Special populations

Linezolid should be used with special caution in patients with severe renal impairment, and only if the expected benefit is considered to outweigh the potential risk (see sections 4.2 and 5.2 of the summary of product characteristics).

Linezolid should be administered to patients with severe hepatic impairment only if the expected benefit is considered to outweigh the potential risk (see sections 4.2 and 5.2).

Effects on fertility

In studies in adult male rats with 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 male reproductive system in humans 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, pressure ulcers, ischaemic 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 medicine contains glucose. If your doctor has informed you that you have an intolerance to certain sugars, consult with him before taking this medicine.

Patients with diabetes mellitus should be aware that this medicine contains 13.7 g of glucose per dose.

Sodium

This medicine contains 114 mg of sodium (the main component of table/cooking salt) per dose. This corresponds to 5.7% of the maximum daily intake of sodium recommended for an adult. Linezolid Normon 2 mg/ml infusion solution may be prepared for administration with solutions containing sodium (see sections 4.2, 6.2 and 6.6), and this should be considered in relation to the total sodium intake from all sources administered to the patient.

Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Data on interaction and safety studies 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 (see sections 4.3 and 4.4).

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 produced mean increases in systolic blood pressure of approximately 30–40 mmHg, compared with 11–15 mmHg with linezolid alone, 14–18 mmHg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mmHg with placebo. Similar studies have not been conducted in hypertensive patients. It is recommended that if linezolid is administered with vasoactive drugs (including dopaminergic agents), their doses should be carefully titrated to achieve the desired response.

Potential serotonergic interactions

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

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

Cases of serotonin syndrome have been reported during clinical concomitant use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids (see section 4.3 of the product information). Therefore, as concomitant administration is contraindicated (see section 4.3 of the product information), section 4.4 describes the management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary.

Use with tyramine-rich foods

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

Medicinal products metabolised via the cytochrome P450 system

Linezolid is not detectably metabolised 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 drug interactions with linezolid are not expected.

Rifampicin

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

Warfarin

Concomitant administration of warfarin and linezolid (at steady state) resulted in a 10% reduction in mean maximum INR (International Normalised 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 (see section 5.3). There is a potential risk in humans.

Linezolid should 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 be excreted in breast milk; therefore, breastfeeding must be discontinued 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 advised that they may experience dizziness or visual disturbances (as described in sections 4.4 and 4.8) while receiving linezolid and should be advised not to drive or operate machinery if either of these symptoms occurs.

Adverse reactions

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

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

The most frequently reported drug-related adverse reactions leading to discontinuation of treatment were headache, diarrhoea, 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, thrombocytopenia*, eosinophilia	sideroblastic anemia*		myelosuppression*
Immune system disorders			anaphylaxis
Metabolism and nutrition disorders		hyponatremia	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 feces, stomatitis, tongue disorders or color changes	discoloration of dental surfaces
Hepatobiliary disorders	abnormal liver function tests; elevated AST, ALT and alkaline phosphatase	elevated 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	elevated BUN	renal failure, increased 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 elevated sodium or calcium. decreased non-fasting glucose. increased or decreased chloride Hematology elevated 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 ischaemic attacks, and hypertension.

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

Paediatric population

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

Reporting suspected adverse reactions

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

Overdose

No specific 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 a dose of linezolid is removed during 3 hours of haemodialysis, but data on removal of linezolid by peritoneal dialysis or haemoperfusion are not available. The two main metabolites of linezolid are also partially removed by haemodialysis.

Signs of toxicity in rats following administration of 3,000 mg/kg/day of linezolid were decreased activity and ataxia, while dogs treated with 2,000 mg/kg/day showed 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 leaks are present, the bag must not be used, as sterility may have been compromised. The solution should be inspected visually before use, and only clear solutions free from particles should be used. Do not use these bags in series connections with other drugs (see section 6.2). Discard any remaining solution.

No special requirements for disposal. Disposal of unused medicine and all materials that have come into contact with it should 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 simultaneously with other drugs, each must be administered separately according to its instructions for use. Similarly, if the same intravenous line is used for sequential intravenous infusion of several drugs, it must be flushed before and after administration of linezolid with a compatible solution.

Linezolid Normon 2 mg/ml is known to be physically incompatible with the following compounds: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and sulfamethoxazole/trimethoprim. In addition, it is chemically incompatible with sodium ceftriaxone.

Shelf life

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 first 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 storage precautions

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.

For storage conditions after first opening, see section 6.3.

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

Detailed information on this medicinal product is available by scanning the QR code included in the package leaflet and carton with a mobile phone (smartphone). Alternatively, this information can be accessed at the following internet address: https://cima.aemps.es/cima/dochtml/p/80679/P_80679.html