Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

ZYVOXID 2 mg/ml solution for infusion

Linezolid

Read all of this 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, including any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet:

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

1. What Zyvoxid is and what it is used for

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

Antibiotics are used to treat bacterial infections and are not effective against viral infections such as influenza or the common cold.

It is important that you follow your doctor's instructions regarding dose, frequency, and duration of treatment.

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

It is used to treat pneumonia and certain skin or subcutaneous tissue infections. Your doctor will have determined whether Zyvoxid is appropriate for treating your infection.

2. What you need to know before using Zyvoxid

Do not use Zyvoxid 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. Zyvoxid passes into breast milk and could affect your baby.

Warnings and precautions

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

Zyvoxid 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 (hyperthyroidism)?
• Do you have a tumor of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumors in the hormonal system, associated with symptoms such as diarrhea, skin flushing, and wheezing)?
• 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 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 Zyvoxid may lead to serotonin syndrome, a potentially life-threatening condition (see section 2 “Other medicines and Zyvoxid” and section 4).

Take special care with Zyvoxid

Inform your doctor before using this medicine if:

• You are elderly.
• You bruise easily or bleed excessively.
• 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:

• Vision problems such as blurred vision, changes in color vision, difficulty seeing clearly, or a reduction in your field of vision.
• Loss of sensation in your arms or legs, or a tingling or burning sensation in your arms or legs.
• Diarrhea may occur while taking or after taking antibiotics, including linezolid. If diarrhea becomes severe, persistent, or if you notice blood or mucus in your stools, stop taking Zyvoxid immediately and consult your doctor. In this situation, you should not take medicines that stop or reduce intestinal movements.
• Repeated nausea or vomiting, abdominal pain, or rapid breathing.
• Muscle pain without apparent cause, tenderness or weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• Malaise and dizziness with muscle weakness, headache, confusion, and memory impairment, which may indicate hyponatremia (low sodium levels in the blood).

Using Zyvoxid with other medicines

Zyvoxid 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 medicine.

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

• 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 Zyvoxid, 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 medications 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.
• 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., 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.

Using Zyvoxid with food, drinks, and alcohol

• You may use Zyvoxid 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 Zyvoxid 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 Zyvoxid in 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 medicine.

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

Driving and using machines

Zyvoxid 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.

Zyvoxid contains glucose

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

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

Zyvoxid contains sodium

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

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

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

3. How to use Zyvoxid

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 as an infusion (given by intravenous drip into a vein). The recommended dose for adults (18 years and older) is 300 ml (600 mg of linezolid) given twice daily directly into the bloodstream (intravenously), administered as an infusion over a period of 30 to 120 minutes.

If you are on a dialysis programme, Zyvoxid should be used 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 Zyvoxid, your doctor will perform periodic blood tests to monitor your blood count.

If you are treated with Zyvoxid for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents

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

If you use more Zyvoxid than you should

If you think you may have been given more Zyvoxid 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: 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to use Zyvoxid

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

4. Possible adverse effects

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

The most serious adverse effects of Zyvoxid (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 Zyvoxid may need to be stopped. 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 colour perception (frequency not known), difficulty seeing fine detail (frequency not known), or if you notice a reduction in your field of vision (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, muscle rigidity, tremor, lack of coordination, convulsions, rapid heartbeat, severe breathing problems, or diarrhoea (symptoms suggestive of serotonin syndrome), especially if you are 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 blood cells that help 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 unexplained muscle pain, tenderness or 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 who have taken Zyvoxid 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, salts, 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 sensation.
• Swelling, discomfort, changes in tongue colour.
• Dry mouth.
• Pain at the injection site (infusion site) or around it.
• Inflammation of veins (including the site where the infusion line is placed).
• Need to urinate more frequently.
• Chills.
• Feeling of thirst.
• Increased sweating.
• Hyponatraemia (low sodium levels in blood).
• Kidney failure.
• Abdominal swelling.
• Pain at injection site.
• Increased creatinine levels.
• 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 1,000 people):

• Change in tooth surface colour, which resolves with professional dental cleaning procedures.

The following adverse effects have also been reported (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: https://www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Zyvoxid

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

Do not use this medicine after the expiry date stated on the carton, sachets, and outer wrapping following "EXP". The expiry date refers to the last day of the month indicated.

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, particle-free solution. Additionally, they will ensure that the solution is stored correctly in its carton and aluminium foil wrapping to protect it from light and to keep it out of the sight and reach of children until use.

After opening:

From a microbiological standpoint, unless the method of opening prevents the risk of microbial contamination, the product should be used immediately. If not used immediately, the time 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 any unused medicines and their packaging. This helps protect the environment.

6. Contents of the pack and other information

Composition of Zyvoxid

• The active substance is linezolid. Each ml of solution contains 2 mg 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 “Zyvoxid contains glucose”), sodium citrate dihydrate (E331, see section 2 “Zyvoxid contains sodium”), anhydrous citric acid (E330), hydrochloric acid (E507), sodium hydroxide (E524), and water for injections.

Appearance of the product and contents of the Zyvoxid pack

Zyvoxid is a clear solution supplied in individual infusion bags containing 300 ml of Zyvoxid.

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

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Pfizer, S.L.

Avda. Europa 20B. Parque Empresarial La Moraleja.

28108, Alcobendas. Madrid, Spain.

Manufacturer

HP Halden Pharma AS.

Svinesundsveien, 80.

1788, Halden.

Norway.

This medicinal product is authorized in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Austria Belgium Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Iceland Ireland Italy Latvia Lithuania Luxembourg Malta Netherlands Norway Poland Portugal Slovakia Slovenia Spain United Kingdom (Northern Ireland) Sweden

Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvox Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvox Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvoxid Zyvox Zyvoxid

Date of the most recent review of this leaflet: June 2024

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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

ZYVOXID 2 mg/ml solution for infusion

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 microorganisms should be initiated if coinfection with gram-negative pathogenic microorganisms is confirmed or suspected.

Description

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

Note: *Currently, only boxes of 10 bags are marketed.

Zyvoxid 2 mg/ml solution for infusion contains linezolid 2 mg/ml in an isotonic, clear, colourless to yellow solution. The other components are: monohydrate glucose, sodium citrate dihydrate (E331), anhydrous citric acid (E330), hydrochloric acid (E507), sodium hydroxide (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 any of the oral formulations when clinically indicated. In such cases, no dose adjustment is required, as the oral bioavailability of linezolid is approximately 100%.

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

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

Recommended duration and dosage for treatment in adults:

The duration of treatment depends on the microorganism, 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.

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, tablets, and granules for oral suspension, and are as follows:

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

Pediatric population: The safety and efficacy of linezolid in children under 18 years of age have not been established. The currently available data are described in sections 4.8, 5.1, and 5.2 of the summary of product characteristics; however, no dosage recommendation can be made.

Elderly patients: Dose adjustment is not required.

Renal impairment: Dose adjustment is not 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 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 hemodialysis, linezolid should be administered after dialysis in patients undergoing this treatment. The main metabolites of linezolid are partially removed by hemodialysis, but their concentrations are considerably higher after dialysis than those observed in patients with normal renal function or mild to moderate renal impairment. Therefore, linezolid should be used with special caution in patients with severe renal 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 hemodialysis).

Hepatic impairment: Patients with mild to moderate hepatic impairment (Child-Pugh Class A or B): Dose adjustment is not required.

Mild to moderate hepatic impairment (Child-Pugh Class C): Since linezolid is metabolized via a non-enzymatic process, it is expected that impaired hepatic function will not significantly alter its metabolism, and therefore dose adjustment is not recommended. However, sufficient clinical data are lacking, 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.

Linezolid must not be used in patients receiving medications that inhibit monoamine oxidase A or B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), nor during the two weeks following discontinuation of such medication.

Unless adequate means are available for close monitoring and control of blood pressure, 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, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar disorder, affective disorders, or acute confusional state.
• Patients taking any of the following medications: serotonin reuptake inhibitors, 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), meperidine, or buspirone.

Animal studies suggest that linezolid and its metabolites may be excreted in breast milk; therefore, breastfeeding must be discontinued before and during treatment (see section 4.6 of the summary of product characteristics).

Special warnings and precautions for use

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in patients treated with linezolid. In patients who were monitored, hematological parameters returned toward 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 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, and in patients with moderate to severe hepatic impairment. Therefore, close monitoring of the complete blood count is recommended in patients who: have pre-existing anemia, granulocytopenia, or thrombocytopenia; are receiving concomitant medications that may reduce hemoglobin levels or 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 treatment for more than 10–14 days. Linezolid should only be administered to these patients if close monitoring of hemoglobin 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, hematological parameters should be closely monitored and appropriate therapeutic measures implemented.

Weekly complete blood counts (including hemoglobin, platelets, absolute leukocyte count, and differential) are also recommended for patients receiving linezolid, regardless of their baseline blood counts.

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

Cases of sideroblastic anemia have been reported during post-marketing experience. In 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 treatment, with or without treatment for anemia.

Mortality imbalance in a clinical trial in patients with catheter-related Gram-positive 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 after discontinuation of the study drug. In the linezolid arm, more patients acquired infections with Gram-negative microorganisms 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.

Diarrhea and antibiotic-associated colitis

Cases of antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhea to fatal colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea 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 treatment 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, anemia, 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, have been reported (see section 4.5 of the summary of product characteristics). Therefore, concomitant administration of linezolid and serotonergic agents is contraindicated (see section 4.3 of the summary of product characteristics), 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.

Rhabdomyolysis

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

Hyponatremia and SIADH

Hyponatremia 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 hyponatremia, 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, occasionally progressing to vision loss, have been reported in patients treated with Zyvoxid; these cases have occurred primarily in patients treated for periods exceeding 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 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. Visual function should be monitored regularly in any patient treated with Zyvoxid for longer than the recommended 28 days.

Continuation of treatment with Zyvoxid in patients who have experienced optic or peripheral neuropathy should be evaluated against potential 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 Zyvoxid. In most of these cases, a history of prior 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 inhibitor of monoamine oxidase (MAOI); however, it has no antidepressant effect at doses used for antibacterial treatment. Data from pharmacological interaction and safety studies of linezolid in patients receiving concomitant medications or with underlying conditions that increase this risk are very limited. Therefore, linezolid is not recommended in such circumstances unless close observation and monitoring of the patient are possible (see sections 4.3 and 4.5 of the summary of product characteristics).

Use with tyramine-rich foods

Patients should be advised not to consume large quantities of tyramine-rich foods.

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 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 of the summary of product characteristics).

Effects on fertility

In studies conducted in adult male rats with exposure levels to linezolid 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.

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, ischemic wounds, severe burns, or gangrene. Therefore, experience with the use of linezolid in the treatment of these conditions is limited.

Excipient warnings

Glucose

This medicinal product contains 45.7 mg of glucose per mL of solution (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 0.02 mmol (0.38 mg) of sodium per mL of solution (4.96 mmol or 114 mg in 300 mL), equivalent to 0.02% of the maximum recommended daily intake (RDI) of 2 g of sodium by WHO for an adult, which should be taken into account in the treatment of patients on sodium-restricted diets.

Zyvoxid 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 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 inhibitor of monoamine oxidase (MAOI). Data from pharmacological interaction and safety studies of linezolid administered to patients receiving concomitant medications with risk of MAO inhibition are very limited. Therefore, linezolid is not recommended in these circumstances unless close observation and monitoring of the patient are possible (see Contraindications and Special warnings and precautions for use).

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 30–40 mm Hg, compared with 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg 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, hyperthermia) were observed.

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

Cases of serotonin syndrome have been reported during clinical co-administration of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, since concomitant administration is contraindicated (see Contraindications), the management of patients for whom treatment with linezolid and serotonergic agents is absolutely necessary is described in the section “Special warnings and precautions for use.”

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.

Medications metabolized via the cytochrome P450 system

Linezolid is not detectably metabolized 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 pharmacological interactions with linezolid are not expected.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult males who 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 Normalized 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. 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 potential 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.

Effects on ability to drive and use machines

Patients should be advised that they may experience dizziness or visual disturbances (as described in the sections “Special warnings and precautions for use” and “Adverse reactions”) while receiving linezolid, and they 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 medicinal product and their frequencies 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 diarrhea (8.9%), nausea (6.9%), vomiting (4.3%), and headache (4.2%).

The most frequently reported drug-related adverse reactions leading to treatment discontinuation were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to an adverse reaction related to the drug.

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).

Organ System Classification	Common (≥1/100 to <1/10)	Uncommon (≥1/1000 to <1/100)	Rare (≥1/10000 to <1/1000)	Very rare (<1/10000)	Frequency not known (cannot be estimated based on 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*, leukopenia*, neutropenia, eosinophilia	sideroblastic anemia*		myelosuppression*
Immune system disorders			anaphylaxis
Metabolism and nutrition disorders		hyponatremia	lactic acidosis*
Psychiatric disorders	insomnia
Nervous system disorders	headache, distorted taste perception (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*, color vision changes*
Ear and labyrinth disorders		tinnitus
Cardiac disorders		arrhythmia (tachycardia)
Vascular disorders	hypertension	transient ischemic attacks, flebitis, thrombophlebitis
Gastrointestinal disorders	diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia	pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, soft stools, stomatitis, tongue discoloration or other tongue disorders	discoloration of dental surface
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
Musculoskeletal and connective tissue disorders			rhabdomyolysis*
Renal and urinary disorders	elevated BUN	renal failure, elevated 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 protein, 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 “Special warnings and precautions for use”.

** See section “Contraindications” and “Interactions with other medicinal products and other forms of interaction”.

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 after the medicine has been authorised. This enables continued monitoring of the benefit-risk balance of the medicine. 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 administered 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 prior to use, and only clear solutions free of particles should be used. Do not use these bags in series connections with other medicines. Discard any remaining solution.

No special requirements for disposal. Disposal of unused medicine and of all materials that have been in contact with it should be carried out in accordance with local regulations.

Do not reuse used bags.

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

Incompatibilities

No additives should be introduced into 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 several drugs, it should be flushed before and after administration of linezolid with a compatible solution.

Zyvoxid infusion solution 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: 3 years.

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 storage times and conditions 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.