Linezolid Altan 2 mg/ml solution for infusion EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Linezolid Altan 2 mg/ml solution for infusion 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, talk to your doctor, pharmacist or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet contents

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

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

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

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

2. What you need to know before using Linezolid Altan

Do not use Linezolid Altan:

• If you are allergic (hypersensitive) to linezolid or to any of the other ingredients of this medicine (listed in section 6).
• If you are taking or have taken within the last 2 weeks any 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.
• If you are breastfeeding. This medicine passes into breast milk and could affect your baby.

Warnings and precautions

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

Linezolid Altan may not be suitable for you if you answer yes to any of the following questions. In such cases, inform your doctor, as they may need to monitor your general health and blood pressure before and during treatment, or may decide that another treatment is more appropriate for you.

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

• Do you have high blood pressure, whether or not you are taking medication for it?
• Have you been diagnosed with hyperactive thyroid?
• Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumours in the hormonal system, presenting symptoms such as diarrhoea, skin flushing, wheezing)?
• Do you suffer from bipolar disorder, schizophrenia, mental confusion, or other mental health problems?
• Do you have a history of hyponatraemia (low levels of sodium in the blood), or are you taking medicines that reduce sodium levels in the blood, such as certain diuretics (also called "water tablets") like hydrochlorothiazide?
• Are you taking any opioids?

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

Take special care with Linezolid Altan

Tell 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.

Tell your doctor or pharmacist 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 stopping antibiotics, including linezolid. If diarrhoea becomes severe, persists for a long time, or if you notice blood or mucus in your stools, stop using Linezolid Altan immediately and consult your doctor. In this situation, do not take medicines that stop or reduce intestinal movements.
• Repeated nausea or vomiting, abdominal pain, or rapid breathing.
• Muscle pain, tenderness, or unexplained weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• Feeling unwell with muscle weakness, headache, confusion, and memory impairment, which may indicate hyponatraemia (low sodium levels in the blood).

Other medicines and Linezolid Altan

Linezolid Altan may sometimes interact with certain medicines and cause adverse effects such as changes in blood pressure, body temperature, or heart rate.

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicine.

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

• 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 Altan, 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 called 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; or certain medicines used to treat opioid dependence, such as buprenorphine. These medicines may interact with linezolid, and you may experience symptoms such as rhythmic and involuntary muscle contractions (including muscles controlling eye movements), agitation, hallucinations, coma, excessive sweating, tremor, exaggerated reflexes, increased muscle tone, and body temperature above 38°C. Contact your doctor if you experience these symptoms.

• 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, for example, pethidine, 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.

Use of Linezolid Altan with food, drinks, and alcohol

• You may use Linezolid Altan before, during, or after meals.
• Avoid eating excessive amounts of cheese, yeast extracts, or soybean extracts (e.g. soy sauce), and avoid alcoholic beverages, especially draught beer and wine. This is because Linezolid Altan may react with a substance called tyramine naturally present in certain foods, causing 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 Altan in pregnant women is unknown. Therefore, pregnant women should not use Linezolid Altan 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.

You should not breastfeed while using Linezolid Altan because this medicine passes into breast milk and could affect your baby.

Driving and using machines

Linezolid Altan 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 use machines may be impaired.

Linezolid Altan contains glucose and sodium

Glucose

This medicine contains glucose.

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

Sodium

This medicine contains 114 mg of sodium (main component in table salt) per 300 ml infusion bag. This amount is equivalent to 5.7% of the maximum recommended daily sodium intake for an adult. Please inform your doctor or nurse if you are on a low-sodium diet.

3. How to use Linezolid Altan.

Adults

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

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

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

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

While you are receiving Linezolid Altan, your doctor will perform periodic blood tests to monitor your blood cell counts.

If you receive Linezolid Altan for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents

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

If you use more Linezolid Altan than you should

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

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

If you forget to use Linezolid Altan

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 take a double dose to make up for a forgotten dose.

4. Possible adverse effects

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

Immediately inform your doctor, nurse, or pharmacist if you notice any of the following side effects during treatment with Linezolid:

The most serious adverse effects of Linezolid (with 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 Altan may need to be discontinued. Skin reactions such as purpuric 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 detail (frequency not known), or reduced visual field (rare).
• Severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis including pseudomembranous colitis), which in rare cases may lead to complications that could be life-threatening (uncommon).
• Repeated nausea or vomiting, abdominal pain, or rapid breathing (rare).
• Cases of epileptic seizures or convulsions have been reported (uncommon).
• Serotonin syndrome (frequency not known). Inform your doctor if you experience agitation, confusion, delirium, stiffness, tremor, lack of coordination, convulsions, rapid heartbeat, severe breathing problems, or diarrhoea (suggestive of serotonin syndrome), especially if you are also being treated with antidepressants called SSRIs or with opioids (see section 2).
• Unexplained bleeding or bruising, which may be due to a disturbance in the number of certain blood cells affecting blood clotting or causing 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).
• Rhabdomyolysis (rare): Signs and symptoms include muscle pain, tenderness or unexplained weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• Inflammation of the pancreas (uncommon).
• Seizures (uncommon).
• Transient ischaemic attacks (temporary disruption of blood flow to the brain causing short-term symptoms such as loss of vision, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
• Ringing in the ears (tinnitus) (uncommon).

Cases of numbness, tingling, or blurred vision have been reported in patients treated with Linezolid Altan 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.
• Changes in certain blood test results, proteins, salts, or enzymes used to assess liver or kidney function, or blood sugar levels.
• Difficulty sleeping.
• Increased blood pressure.
• Anaemia (reduced number of red blood cells).
• Itching.
• Dizziness.
• General or localized abdominal pain.
• Constipation.
• Indigestion.
• Localized pain.
• Decreased platelet count.

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

• Inflammation of the vagina or female genital area.
• Tingling or numbness sensation.
• Swelling, discomfort, changes in tongue color.
• Dry mouth.
• Pain at or around the injection site.
• Vein inflammation (including at the site where the infusion line is placed).
• Need to urinate more frequently.
• Chills.
• Thirst sensation.
• Increased sweating.
• Hyponatremia (low sodium levels in the blood).
• Kidney failure.
• Abdominal swelling.
• Pain at injection site.
• Increased creatinine.
• Stomach pain.
• Changes in heart rhythm (e.g., increased heart rate).
• Decreased blood cell count.
• Weakness and/or sensory changes.

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

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

Not known (frequency cannot be estimated from available data):

• Alopecia (hair loss)

Reporting of adverse effects

If you experience any type of 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: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Linezolid Altan

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

Do not use this medicine after the expiry date stated on the pack after “EXP”. The expiry date is the last day of the month indicated.

Do not freeze.

Hospital staff will ensure that Linezolid Altan is not used after the printed use-by date and that it is administered immediately after breaking the seal. They will also visually inspect the solution before use and use it only if it is clear and free from particles. They will also ensure that the solution is properly stored in its container and within its aluminium foil wrapper to protect it from light and keep it out of the sight and reach of children until use.

After opening:

From a microbiological point of view, unless the method of opening prevents the risk of microbial contamination, the product should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This helps protect the environment.

6. Contents of the pack and other information

Composition of Linezolid Altan

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

The other components are monohydrate glucose (a type of sugar, see section 2. Linezolid Altan contains glucose), sodium citrate (E331, see section 2), anhydrous citric acid (E330), hydrochloric acid (E507) or sodium hydroxide (E524) to adjust pH, and water for injections.

Appearance of the product and contents of the pack

Linezolid Altan is a clear solution supplied in single-use infusion bags containing 300 ml (600 mg of linezolid) of solution.

The bags are available in packs of 1, 10 or 25 bags.

Not all pack sizes may be marketed.

Marketing Authorization Holder

Altan Pharmaceuticals, S.A.
C/ Cólquide, Nº 6, Portal 2, 1st floor, Office F. Prisma Building
Las Rozas, 28230 Madrid, Spain

Manufacturer

Infomed Fluids S.R.L
50 Theodor Pallady blvd, District 3,
032266 Bucharest, Romania
Tel: +40 21 345 02 22
Fax: +40 21 345 3185
E-mail: [email protected]

This medicinal product has been authorized in EU Member States and in the United Kingdom (Northern Ireland) under the following names:

France: Linezolid Panpharma 2 mg/ml Solution for Infusion
Germany: Linezolid Panpharma 2 mg/ml Infusionslösung
Romania: Linezolid Infomed 2 mg/ml solution for infusion
Spain: Linezolid Altan 2 mg/ml solution for infusion EFG

Date of the most recent review of this package leaflet:
March 2025

Detailed and up-to-date 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/

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This information is intended for healthcare professionals only:

IMPORTANT: Consult the summary of product characteristics before prescribing.

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

Description

Single-use, latex-free, multilayer polyolefin sealed infusion bags with an outer laminated aluminum pouch. Each bag contains 300 ml of solution and is presented in a pack. Each pack contains 1, 10 or 25 intravenous infusion bags.

Linezolid Altan 2 mg/ml solution for infusion contains linezolid 2 mg/ml in an isotonic, clear, colorless to yellow solution. The other components are: monohydrate glucose, sodium citrate (E331), anhydrous citric acid (E330), hydrochloric acid (E507) or sodium hydroxide (E524), and water for injections.

Dosage 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 any of the oral formulations when clinically indicated. In such cases, dosage adjustment is not required, as the oral bioavailability of linezolid is approximately 100%.

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

The recommended dose of linezolid should be administered intravenously (IV) twice daily.

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

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid have not been established when administered for periods exceeding 28 days (see section 4.4).

Bacteraemia-associated infections do not require an increase in the recommended dose or duration of treatment. The recommended doses of linezolid are as follows:

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-fold) of the two main metabolites of linezolid in these patients is unknown, this medicinal product should be used with special caution in patients with severe renal impairment and should only be administered 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 failure (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 deterioration in hepatic function will not significantly alter its metabolism and therefore dose adjustment is not recommended. However, sufficient clinical data are not available and linezolid should be used in these patients only if the expected benefit outweighs the theoretical risk (see sections 4.4 and 5.2 of the Summary of Product Characteristics).

Contraindications

Hypersensitivity to linezolid or to any of the excipients 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), nor within two weeks of stopping such medication.

Unless adequate means are available for close monitoring and blood pressure surveillance, 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, psychoaffective 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 agents (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).

Warnings and special precautions for use

Marrow suppression

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 related to the duration of treatment. Elderly patients receiving linezolid may be at increased risk of developing blood dyscrasias compared to younger patients. Thrombocytopenia may occur more frequently in patients with severe renal impairment, whether or not undergoing dialysis, and in patients with moderate to severe hepatic impairment. Therefore, close monitoring of the full blood count is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may reduce haemoglobin levels and red blood cell count or that may reduce or adversely affect platelet count or function; have severe renal impairment or moderate to severe hepatic impairment; or are receiving more than 10–14 days of treatment. Linezolid should only be administered to these patients if close monitoring of haemoglobin levels, blood counts and platelet counts is possible.

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

A complete blood count (including haemoglobin, platelets, absolute white blood cell count and differential) should also be performed weekly in all patients receiving linezolid, regardless of baseline haematological status.

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

Cases of sideroblastic anaemia have been reported during post-marketing experience. In cases where onset time was known, most patients had been treated for more than 28 days. Most patients recovered fully or partially after discontinuation of linezolid, 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 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 after discontinuation of the study drug. In the linezolid arm, more patients acquired Gram-negative microorganism 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 alternative treatments are available (see section 4.1). In such circumstances, concomitant therapy against Gram-negative microorganisms should be initiated.

Antibiotic-associated diarrhoea and 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. Medications that inhibit peristalsis are contraindicated in this situation.

Lactic acidosis

Cases of lactic acidosis have been reported with the use of linezolid. Patients who develop signs or symptoms of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation, while being treated with linezolid should receive immediate medical attention. If lactic acidosis occurs, the benefits of continuing linezolid therapy should be weighed against potential risks.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse events such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur; these events are more frequent when treatment duration exceeds 28 days.

Serotonin syndrome

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

The occurrence of serotonin syndrome has also been associated with concomitant administration of linezolid and buprenorphine.

Rhabdomyolysis

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

Hyponatraemia and SIADH

Hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients treated with linezolid. Serum sodium levels should be monitored regularly in patients at risk of hyponatraemia, such as elderly patients or those 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, sometimes progressing to vision loss, have been reported in patients treated with linezolid; these cases have occurred primarily in patients treated for periods exceeding the recommended maximum duration of 28 days.

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

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

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

Seizures

Cases of seizures have been reported in patients treated with Linezolid Altan. 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 exerts no antidepressant effect at doses used for antibacterial treatment. Data on pharmacological interaction and safety studies of linezolid in patients receiving concomitant medications that increase this risk are limited. Therefore, linezolid should not be used in such circumstances unless close observation and monitoring of the patient are possible (see sections 4.3 and 4.5).

Use with tyramine-rich foods

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

Superinfection

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

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

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).

It is recommended that linezolid be administered to patients with severe hepatic impairment only if the expected benefit outweighs the potential risk (see sections 4.2 and 5.2).

Effects on fertility

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

Each ml of solution contains 45.7 mg of glucose (13.7 g in 300 ml), which should be taken into account in the treatment of patients with diabetes mellitus.

Sodium

This medicinal product contains 114 mg of sodium per 300 ml infusion bag (0.38 mg/ml), equivalent to 5.7% of the maximum daily sodium intake recommended by the WHO of 2 g sodium for an adult. Sodium content should be considered in patients on a sodium-restricted diet.

Linezolid infusion solution may additionally 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 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 pharmacological 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 causing 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 to 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

In healthy volunteers, the potential for pharmacological interaction between linezolid and dextromethorphan was studied. 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 and 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.

Linezolid should be used with caution when administered concomitantly with buprenorphine due to increased risk of serotonin syndrome, a potentially life-threatening condition (see section 4.4 of the Summary of Product Characteristics).

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

Use with tyramine-rich foods

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

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 clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, CYP450-mediated pharmacokinetic interactions with linezolid are not expected.

Rifampicin

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

Warfarin

Concomitant administration of warfarin and linezolid (at steady state) resulted in a 10% reduction in mean maximum INR (International Normalised Ratio) and a 5% decrease in 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 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

In the following table, all adverse reactions of this medicinal product and their frequencies are listed, based on all causality data from clinical trials involving over 6,000 adult patients who received the recommended doses of linezolid for up to 28 days. The most frequently reported adverse reactions were diarrhoea (8.49%), nausea (6.9%), vomiting (4.3%) and headache (4.2%).

The most frequently reported drug-related adverse reactions leading to treatment discontinuation 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.

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).

1 See section 4.4 Warnings and special precautions for use

2 See section 4.3 Contraindications and 4.5 Interaction with other medicinal products and other forms of interaction

3 See below

#Frequency of ADRs (Adverse Drug Reactions) estimated using the "rule of three".

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

3 In controlled clinical trials where linezolid was administered for treatment periods of up to 28 days, 2% of patients reported anaemia. In a compassionate use program of 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 to 12.3% (53/430) when treated for > 28 days. The proportion of reported cases of severe drug-related anaemia requiring blood transfusion was 9% (3/33) in patients treated ≤ 28 days and 15% (8/53) in those treated for more than 28 days.

Paediatric population

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

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing 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 the dose of linezolid is removed during 3 hours of haemodialysis, but data on elimination 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 after 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 medicinal products (see section 6.2). Discard any remaining solution.

Do not reuse used bags.

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

Incompatibilities

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

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

Expiry date

Before opening: 24 months.

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

Special precautions for storage

Keep the outer bag in the original packaging (aluminium bag and cardboard) to protect it from light until the time of use.