Prospecto: Information for the User

ZYVOXID 2 mg/ml Infusion Solution

Linezolid

Read this prospectus carefully before starting to use this medication,because it contains important information for you.

• Keep this prospectus, as you may need to read it again.
• If you have any doubts, consult your doctor, pharmacist, or nurse.
• If you experience adverse effects, consult your doctor, pharmacist, or nurse,even if they are not listed in this prospectus. See section 4.

1.What Zyvoxid is and for what it is used

2.What you need to knowbefore starting touse Zyvoxid

3.How to use Zyvoxid

4.Possible adverse effects

5.Storage of Zyvoxid

6. Contents of the package and additional information

Zyvoxid is an antibiotic belonging to the oxazolidinones group that acts 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 if Zyvoxid is suitable for treating your infection.

Do not use Zyvoxid if:

• You are allergic to linezolid or any of the other components of this medication (including those listed in section6).
• You are taking or have taken in the last 2weeks any medication called monoamine oxidase inhibitors (MAOIs such as, for example, phenelzine, isocarboxazid, selegiline, moclobemide). These medications are usually used to treat depression or Parkinson's disease.
• You are breastfeeding. Zyvoxid passes into the milk and could affect the baby.

Warnings and precautions

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

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

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

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

The use of certain medications, including antidepressants and opioids, with Zyvoxid may cause serotonin syndrome, a potentially life-threatening condition (see section2 “Other medications and Zyvoxid” and section4).

Be especially careful with Zyvoxid

Inform your doctor before using this medication if:

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

Inform your doctor immediately if during treatment you experience:

• Visual problems such as blurred vision, changes in color vision, difficulty seeing clearly, or if you notice a reduction in your field of vision.
• Loss of sensation in your arms or legs or a feeling of tingling or burning in your arms or legs.
• Dysentery may occur while taking or after taking antibiotics, including linezolid. If diarrhea becomes intense, lasts a long time, or if you notice that your stools contain blood or mucus, stop taking Zyvoxid immediately and consult your doctor. In this situation, do not take medications that stop or reduce intestinal movements.
• Recurring nausea or vomiting, abdominal pain, or rapid breathing.
• Muscle pain without apparent cause, sensitivity, and/or weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle degradation), which can cause kidney damage.
• Discomfort and dizziness with muscle weakness, headache, confusion, and memory deterioration that may indicate hyponatremia (low sodium levels in the blood).

Using Zyvoxid with other medications

In some cases, Zyvoxid may interact with certain medications and produce adverse effects such as changes in blood pressure, body temperature, or heart rate.

Inform your doctor or pharmacist if you are taking or have taken recently any other medication.

Inform your doctor if you are taking or have taken in the last 2 weeksthe following medications, asyou should notuse Zyvoxid if you are still taking them or if you have taken them recently (see also the section2 above “Do not use Zyvoxid”).

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

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

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

Using Zyvoxid with food, drinks, and alcohol

• You can take Zyvoxid before, during, or after meals.
• Avoid eating large amounts of cheese, yeast extracts, or soybean extracts (such as soy sauce) and alcoholic beverages, especially barrel beer and wine. The reason is that Zyvoxid may react with a substance called tyramine that is naturally present in some foods. This interaction may cause an increase in your blood pressure.
• If you start with a headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility

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

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

Driving and operating machines

Zyvoxid may cause dizziness or visual problems. If this happens, do not drive or operate machines. Remember that if you do not feel well, you may be affected in your ability to drive or operate machines.

Zyvoxid contains glucose

This medication contains glucose. Patients with diabetes mellitus should be aware that this medication contains 13.7g of glucose per vial.

1ml of Zyvoxid solution contains 45.7mg of glucose (13.7g of glucose in a vial). Please inform your doctor or nurse if you are diabetic.

Zyvoxid contains sodium

Patients on low-sodium diets should be aware that this medication contains 114mg (4.96 mmol) of sodium per vial.

1ml of Zyvoxid solution contains 0.38mg of sodium (main component of table salt/for cooking) (114mg of sodium in a vial). The sodium in a vial is equivalent to 5.7% of the maximum daily sodium intake recommended for an adult.

Please inform your doctor or nurse if you are following a low-sodium diet.

Adults

Follow exactly the medication administration instructions contained in this leaflet or those indicated by your doctor, pharmacist, or nurse. If in doubt, ask your doctor, pharmacist, or nurse.

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

If you are on dialysis, use Zyvoxid after each session.

The normal duration of treatment is 10-14 days, but it may be extended up to 28 days. The safety and efficacy of this medication have not been established in treatment periods exceeding 28 days. Your doctor will decide the duration of your treatment.

While using Zyvoxid, your doctor will perform periodic blood tests to monitor your blood count.

If you take Zyvoxid for more than 28 days, your doctor should monitor your vision.

Use in children and adolescents

Zyvoxid is not usually used in children or adolescents (under 18 years).

If you take more Zyvoxid than you should

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

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

If you forgot to use Zyvoxid

As this medication is administered under close supervision, it is very unlikely that a dose will be forgotten. If you think you have forgotten to administer a dose of treatment, inform your doctor or nurse. Do not take a double dose to compensate for the missed dose.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.personas los sufran.

The most serious side effects of Zyvoxid (frequency in parentheses) are:

• Severe skin changes (rare), swelling, particularly around the face and neck (rare), shortness of breath and/or difficulty breathing (rare). This may be a sign of an allergic reaction and treatment with Zyvoxid may need to be discontinued. Skin reactions such as purple raised rash due to inflammation of blood vessels (rare), red, painful, and scaly skin (dermatitis) (rare), skin rash (frequent), itching (frequent).
• Visual problems (rare), such as blurred vision (rare), changes in color perception (unknown), difficulty seeing details (unknown), or if you notice a reduction in your field of vision (rare).
• Severe diarrhea that contains blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare cases may lead to complications that can be life-threatening (rare).
• Recurring nausea or vomiting, abdominal pain, or rapid breathing (rare),
• There have been reported cases of seizures or convulsions (rare).
• Serotonin syndrome (unknown) should inform your doctor if you experience agitation, confusion, delirium, rigidity, tremors, discoordination, convulsions, rapid heart rate, severe respiratory problems, and diarrhea (suggestive of serotonin syndrome) while also being treated with antidepressants called ISRSs or opioids (see section2).
• Unexplained bleeding or bruising, which may be due to an alteration in the number of certain blood cells that can affect blood clotting or produce anemia (frequent).
• Reduction in the number of white blood cells that can affect the ability to fight infections (rare). Some signs of infection include: fever (frequent), sore throat (rare), mouth ulcers (rare), and fatigue (rare).
• Rhabdomyolysis (rare): symptoms and signs include unexplained muscle pain, sensitivity, or weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle degradation), which can cause kidney damage.
• Pancreatitis (rare).
• Convulsions (rare).
• Transient ischemic attacks. (Temporary alteration of blood flow to the brain that causes short-term symptoms such as loss of vision, weakness in arms and legs, difficulty speaking, and loss of consciousness) (rare).
• Tinnitus (ringing in the ears) (rare).

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

Other side effects include:

Frequent (may affect up to1 in 10people):

• Fungal infections, especially in the vagina or mouth.
• Headache.
• Metalllic taste.
• Diarrhea, vomiting, nausea.
• Alteration of some blood test results, including protein, salt, or enzyme tests that measure liver, kidney, or blood sugar function.
• Difficulty sleeping.
• Increased blood pressure.
• Anemia (reduction in the number of red blood cells).
• Itching.
• Dizziness.
• Abdominal pain, localized or generalized.
• Constipation.
• Indigestion.
• Localized pain.
• Reduction in platelet count.

Rare (may affect up to1 in 100people):

• Vaginal or genital area inflammation in women.
• Sensation of numbness or tingling.
• Swelling, discomfort, changes in color of the tongue.
• Dry mouth.
• Pain at the injection site (route) or around it.
• Phlebitis (inflammation of veins, including the location where the infusion is administered).
• Increased frequency of urination.
• Chills.
• Thirst.
• Increased sweating.
• Hyponatremia (low sodium levels in blood).
• Renal failure.
• Abdominal swelling.
• Pain at the 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 to1 in 1000people):

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

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

• Alopecia (hair loss).

Reporting of side effects

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

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

Do not use this medication after the expiration date that appears on the box, bags, and outer packaging after “CAD”. The expiration date is the last day of the month indicated.

The hospital staff will ensure that Zyvoxid Solution is not used after the use-by date printed on the bag and that it is administered immediately after breaking the seal. They will also visually inspect the solution before use and only use it if it is a clear and particle-free solution.They will also ensure that the solution is properly stored in its box and aluminum foil packaging to protect it from light and keep it out of sight and reach of children until use.

After opening:

From a microbiological standpoint, unless the opening method prevents the risk of microbial contamination, the product must be used immediately. If not used immediately, the time and storage conditions are the responsibility of the user.

Medications should not be disposed of through the drains or trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of Zyvoxid

• The active ingredient is linezolid. Eachml of solution contains 2mg of linezolid. Each 300ml infusion bag contains 600mg of linezolid.
• The other components are glucose monohydrate (a type of sugar, see section2 “Zyvoxid contains glucose”), sodium citrate dihydrate (E331, see section2 “Zyvoxid contains sodium”), anhydrous citric acid (E330), hydrochloric acid (E507), sodium hydroxide (E524), and water for injection.

Appearance of the product and contents of the Zyvoxid packaging

Zyvoxid is a transparent solution that is presented in individual infusion bags containing 300ml of Zyvoxid.

The bags are presented in packs of 1, 2, 5, 10, 20, or 25bags.

Not all pack sizes may be marketed.

Marketing authorisation holder and responsible manufacturer

Marketing authorisation holder

Pfizer, S.L.

Avda. Europa 20B. Parque Empresarial La Moraleja.

28108, Alcobendas. Madrid, Spain.

Responsible manufacturer

HP Halden Pharma AS.

Svinesundsveien, 80.

1788, Halden.

Norway.

This medicinal product is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) with the following names:

Last update of this leaflet: June 2024

The detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

GUIDE FOR PROFESSIONALS. The following information is intended only for healthcare professionals:

ZYVOXID 2mg/ml solution for infusion

Linezolid

IMPORTANT: Consult the technical data sheet before prescribing.

Linezolid is not active against infections caused by Gram-negative pathogenic microorganisms. Concomitant treatment with antibiotics effective against Gram-negative microorganisms should be initiated if there is certainty or suspicion of coinfection with Gram-negative pathogenic microorganisms.

Description

Single-use intravenous infusion bags, latex-free, multi-layered polyolefin (Excel or Freeflex) sealed, with an outer aluminium laminated bag. Each bag contains 300ml of solution and is presented in a box. Each box contains 1, 2, 5, 10*, 20, or 25intravenous infusion bags.

Nota: *Currently only 10-bag boxes are marketed.

Zyvoxid 2mg/ml solution for infusion contains linezolid 2mg/ml in an isotonic, transparent, yellowish-transparent solution. The other components are:glucose monohydrate, sodium citrate dihydrate (E331), anhydrous citric acid (E330), hydrochloric acid (E507), sodium hydroxide (E524), and water for injection.

Dosage and administration

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

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

The solution for infusion should be administered over a period of 30to120minutes.

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

Duration and recommended dosing for adult treatment:

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

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

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

Infections associated with bacteremia do not require an increase in the recommended dose or treatment duration. The recommended doses are the same for the solution for infusion, tablets, and oral granules suspension and are as follows:

Pediatric population:No safety and efficacy have been established in children under 18years. The available data are described in sections4.8, 5.1, and5.2 of the technical data sheet, but no posological recommendation can be made.

Geriatric patients::No dose adjustment is required.

Renal impairment:No dose adjustment is required.

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

Since approximately 30% of the linezolid dose is eliminated during 3hours of haemodialysis, linezolid will be administered after dialysis in patients receiving this treatment. The main metabolites of linezolid are eliminated in part by haemodialysis, but their concentrations are significantly higher after dialysis than in patients with normal renal function or mild to moderate renal impairment. Therefore, linezolid will be used with special caution in patients with severe renal impairment undergoing dialysis and only if the expected benefit outweighs the potential risk.

There is no experience with the administration of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal impairment (other than haemodialysis).

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

Mild to moderate hepatic impairment (Class C in the Child-Pugh scale):As linezolid is metabolized by a non-enzymatic process, it is expected that impaired liver function will not significantly alter its metabolism, and therefore no dose adjustment is recommended. However, there are insufficient clinical data, and linezolid should only be used in these patients if the expected benefit outweighs the potential risk.

Contraindications

Hypersensitivity to linezolid or any of the excipients.

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

Unless adequate means are available to perform close monitoring of blood pressure, linezolid should not be administered to patients with the following underlying clinical conditions or those receiving the following medications:

• Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, affective disorders, or acute confusional state.
• Patients taking any of the following medications: selective serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1receptor agonists (triptans), direct or indirect sympathomimetics (including bronchodilators, pseudoephedrine, and phenylpropanolamine), vasopressors (e.g., epinephrine, norepinephrine), dopaminergic drugs (e.g., dopamine, dobutamine), meperidine, or buspirone.

The data from animal studies suggest that linezolid and its metabolites may pass into breast milk, so breastfeeding should be discontinued before and during treatment (see section4.6 of the technical data sheet).

Special warnings and precautions for use

Myelosuppression

Myelosuppression (including anemia, leucopenia, pancytopenia, and thrombocytopenia) has been reported in patients treated with linezolid. In patients who were monitored, the affected hematological parameters returned to pre-treatment levels after treatment was discontinued. The risk of these effects appears to be associated with the duration of treatment. Elderly patients treated with linezolid may be at a higher risk of experiencing hematological disorders than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal impairment, whether or not they are undergoing dialysis, and in patients with moderate to severe hepatic impairment. Therefore, close monitoring of the hemogram is recommended in patients who:

• Have pre-existing anemia, granulocytopenia, or thrombocytopenia;
• Are receiving concomitant medication that may decrease hemoglobin levels and hematocrit or reduce the platelet count or affect platelet function;
• Have severe renal impairment or moderate to severe hepatic impairment;
• Are receiving more than 10-14days of treatment.

Linezolid should only be administered to these patients if it is possible to perform close monitoring of hemoglobin, blood cell count, and platelet levels.

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

It is also recommended that a complete blood count (including hemoglobin, platelets, absolute leucocyte count, and formula) be performed weekly in patients receiving linezolid, regardless of their baseline hemogram.

In compassionate use studies, a higher incidence of severe anemia was reported in patients treated with linezolid for periods longer than the recommended maximum treatment duration of 28days. These patients required more frequent blood transfusions. Cases of anemia requiring blood transfusion have also been reported during post-marketing experience, with a higher number of cases in patients treated with linezolid for more than 28days.

Severe anemia has been reported during post-marketing experience, including cases requiring blood transfusion. The majority of patients were treated for more than 28days. Most patients recovered partially or completely after discontinuation of linezolid, with or without treatment for anemia.

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

In an open-label study in severely ill patients with catheter-related Gram-positive 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 rates was the baseline status of Gram-positive infection. Mortality rates were similar in patients with infections caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58-1.59), but were significantly higher (p = 0.0162) in the linezolid arm for patients infected with any other microorganism or in whom no baseline microorganism was isolated (odds ratio 2.48; 95% CI: 1.38-4.46). The greatest imbalance occurred during treatment and within 7days after discontinuation of the study drug in the linezolid arm. In the linezolid arm, more patients acquired Gram-negative infections during the study and died from Gram-negative infections and polymicrobial infections. Therefore, linezolid should only be used in patients with complicated skin and soft tissue infections in whom there is suspicion or certainty of coinfection with Gram-negative microorganisms if no other treatment options are available (see section4.1). In these circumstances, concomitant treatment with antibiotics effective against Gram-negative microorganisms should be initiated.

Diarrhea and antibiotic-associated colitis

With the use of almost all antibiotics, including linezolid, cases of antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported, with varying severity from mild diarrhea to life-threatening colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with linezolid. If suspected or confirmed antibiotic-associated diarrhea or colitis, treatment with antibiotics, including linezolid, should be discontinued and appropriate therapeutic measures should be implemented immediately. In this situation, medications that inhibit peristalsis are contraindicated.

Lactic acidosis

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

Mitochondrial dysfunction

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

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the concomitant administration of linezolid and serotoninergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, have been reported. Therefore, concomitant administration of linezolid and serotoninergic agents is contraindicated (see section4.3 of the technical data sheet), except when the concomitant administration of linezolid and serotoninergic agents is absolutely necessary. In these cases, patients should be closely monitored for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and ataxia. If signs or symptoms occur, discontinuation of one or both agents should be considered; if the serotoninergic agent is discontinued, symptoms may resolve.

Rhabdomyolysis

Rhabdomyolysis has been reported with the use of linezolid. Linezolid should be used with caution in patients with risk factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, treatment with linezolid should be discontinued and appropriate therapeutic measures should be implemented.

Hypontremia and SIADH

Hypontremia 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 hypontremia, such as elderly patients or patients taking medications that may reduce serum 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 may progress to loss of vision, have been reported in patients treated with Zyvoxid; these cases have occurred primarily in patients treated for periods longer than the recommended maximum duration of 28days.

Patients should be advised to report any symptoms of visual disturbances, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defects. In such cases, visual function should be evaluated as soon as possible, and an ophthalmologist should be consulted if necessary. Regular monitoring of visual function is recommended in any patient treated with Zyvoxid for a period longer than the recommended 28days.

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

A higher risk of neuropathy may exist when linezolid is used in patients who are currently taking or have recently taken antimycobacterial medication for tuberculosis treatment.

Seizures

Cases of seizures have been reported in patients treated with Zyvoxid. In most cases, a history of seizures or risk factors for seizures was reported. Patients should be advised to report any history of seizures.

MAOIs

Linezolid is a reversible and non-selective monoamine oxidase (MAO) inhibitor; however, it does not exhibit any antidepressant effect at the doses used for antibacterial treatment. Limited data are available on the pharmacological and safety interactions of linezolid in patients receiving linezolid and underlying pathologies or concomitant treatment with medications that increase the risk of these interactions. Therefore, linezolid should not be used in these circumstances, except when close monitoring and observation of the patient are possible (see sections4.3 and4.5 of the technical data sheet).

Use with foods rich in tyramine

Patients should be advised not to consume large amounts of foods rich in tyramine.

Superinfection

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

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

Special populations

Linezolid should be used with caution in patients with severe renal impairment and only if the expected benefit outweighs the potential risk (see sections4.2 and5.2 of the technical data sheet).

Linezolid should only be used in patients with severe hepatic impairment if the expected benefit outweighs the potential risk (see sections4.2 and 5.2 of the technical data sheet).

Effects on fertility

In studies with adult male rats, linezolid caused a reversible decrease in fertility and abnormal sperm morphology. The potential effects of linezolid on human male reproductive system are unknown.

Clinical trials

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

Clinical trials did not include patients with diabetic foot lesions, pressure ulcers, ischemic lesions, severe burns, or gangrene. Therefore, there is limited experience with the use of linezolid in the treatment of these conditions.

Warnings about excipients

Glucose

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

Sodium

This medicinal product contains 0.02mmol (0.38mg) of sodium per eachml of solution (4.96mmol or 114mg in 300ml), which is equivalent to 0.02% of the maximum daily recommended intake (RDI) of 2g of sodium per day by the WHO for an adult,which should be taken into account in the treatment of patients with low-sodium diets.

Zyvoxid solution for infusion may be prepared for administration with solutions containing sodium (see sections4.2, 6.2, and6.6) and this should be considered in relation to the total sodium intake from all sources administered to the patient.

Interactions with other medicinal products and other forms of interaction

MAOIs

Linezolid is a reversible and non-selective monoamine oxidase (MAO) inhibitor. Limited data are available on the pharmacological and safety interactions of linezolid in patients receiving linezolid and underlying pathologies or concomitant treatment with medications that increase the risk of these interactions. Therefore, linezolid should not be used in these circumstances, except when close monitoring and observation of the patient are possible (see Contraindications and Special warnings and precautions for use).

Potential interactions that increase blood pressure

Linezolid increased the hypertensive effect produced by pseudoephedrine and phenylpropanolamine in healthy normotensive volunteers. Simultaneous administration of linezolid with pseudoephedrine or phenylpropanolamine produced mean increases in systolic blood pressure of approximately 30-40mmHg, compared with the 11-15mmHg produced by linezolid alone, the 14-18mmHg produced by pseudoephedrine or phenylpropanolamine alone, and the 8-11mmHg produced by the placebo. No similar studies have been performed in hypertensive patients. It is recommended that if linezolid is administered with vasopressor medications (including dopaminergic agents), the doses of these medications should be titrated carefully to achieve the desired response.

Potential serotoninergic interactions

In healthy volunteers, the potential pharmacological interaction of linezolid with dextromethorphan was studied. Two doses of 20mg of dextromethorphan were administered with a 4hour interval, with or without linezolid. In healthy volunteers who received linezolid and dextromethorphan, no serotoninergic syndrome effects were observed.

During post-marketing experience, a case of a patient experiencing symptoms similar to those of serotoninergic syndrome was reported while taking linezolid and dextromethorphan, which resolved after discontinuation of both treatments.

Reports of serotoninergic syndrome have been reported during the concomitant use of linezolid with serotoninergic agents, including antidepressants such as SSRIs and opioids. Therefore, concomitant administration of linezolid and serotoninergic agents is contraindicated (see Contraindications), except when the concomitant administration of linezolid and serotoninergic agents is absolutely necessary. In these cases, patients should be closely monitored for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and ataxia. If signs or symptoms occur, discontinuation of one or both agents should be considered; if the serotoninergic agent is discontinued, symptoms may resolve.

Use with foods rich in tyramine

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

Medicinal products metabolized through cytochrome P450

Linezolid is not metabolized to a detectable extent by the cytochrome P450 (CYP) enzyme system or inhibits any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Similarly, linezolid does not induce CYP enzymes in rats. Therefore, no CYP450-induced pharmacological interactions are expected with linezolid.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male volunteers who received 600mg of linezolid twice a day for 2.5days, with and without 600mg of rifampicin once a day for 8days. 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

The concomitant administration of warfarin and linezolid (in steady-state) produced a 10% mean maximum reduction in INR and a 5% reduction in AUC of INR. The available 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

The available data on the use of linezolid in pregnant women are limited. Animal studies have shown reproductive toxicity. A potential risk in humans exists.

Linezolid should not be used during pregnancy, except when clearly necessary. That is, only if the potential benefit outweighs the potential risk.

Lactation

Animal data suggest that linezolid and its metabolites may pass into breast milk, so breastfeeding should be discontinued before and during treatment.

Fertility

Studies in animals have shown a decrease in fertility.

Effects on the ability to drive and use machines

Patients should be advised that they may experience dizziness or visual disturbances (as described in the Special warnings and precautions for use and Adverse reactions sections) while receiving linezolid, and they should be advised not to drive or operate machinery if any of these symptoms occur.

Adverse reactions

The following table lists all adverse reactions to this medicinal product and their frequencies based on all causality data from clinical trials in which more than 6,000 adult patients received the recommended doses of linezolid for up to 28days. The most frequently reported adverse reactions were diarrhea (8.9%), nausea (6.9%), vomiting (4.3%), and headache (4.2%).

The adverse reactions related to the medicinal product most frequently reported that required discontinuation of treatment were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to an adverse