Package leaflet: Information for the user

LINEZOLID S.A.L.F. 2mg/ml infusion solution

Linezolid
Please read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
If you get any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.
Contents of this leaflet:

What Linezolid S.A.L.F. is and what it is used for
What you need to know before being treated with Linezolid S.A.L.F.
How to take Linezolid S.A.L.F.
Possible side effects
How to store Linezolid S.A.L.F.
Contents of the pack and other information

1. What Linezolid S.A.L.F. is and what it is used for

Linezolid S.A.L.F. is an antibiotic belonging to the oxazolidinone class, which works by inhibiting the growth of certain bacteria (germs) that cause infections. It is used to treat pneumonia and certain skin or soft tissue infections. Your doctor will decide whether Linezolid S.A.L.F. is suitable for treating your type of infection.

2. What you need to know before being treated with Linezolid S.A.L.F.

Do not take Linezolid S.A.L.F.:

if you are allergic 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 of the medicines known as monoamine oxidase inhibitors (MAOIs), for example phenelzine, isocarboxazid, selegiline, moclobemide. These are medicines generally used to treat depression or Parkinson’s disease.
if you are breastfeeding. Linezolid S.A.L.F. passes into breast milk and may affect the infant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before taking Linezolid S.A.L.F.
Linezolid S.A.L.F. may not be suitable for you if you answer “yes” to any of the following questions. In such cases, inform your doctor, who may need to monitor your general health and blood pressure before and during treatment, or may decide that an alternative therapy is better for you.
Ask your doctor if you are unsure whether any of these conditions apply to you.

Do you have high blood pressure, whether or not you are taking medication for it?
Have you been diagnosed with hyperthyroidism (overactive thyroid)?
Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by hormone-producing tumours, with symptoms such as diarrhoea, skin flushing, and wheezing)?
Do you suffer from manic depression, schizoaffective disorder, confusion, or any other mental disorder?
Do you have a history of hyponatraemia (low sodium levels in the blood), or are you taking medicines that lower sodium levels in the blood, e.g. certain diuretics (also called “water pills”) such as hydrochlorothiazide?
Are you taking opioids?

The use of certain medicines, including antidepressants and opioids, together with Linezolid S.A.L.F. may lead to the development of serotonin syndrome, a potentially life-threatening condition (see section 2 “Other medicines and Linezolid S.A.L.F.” and section 4).

Be especially careful with Linezolid S.A.L.F.

Inform your doctor before taking this medicine if:

you are elderly
you are prone to bruising or episodes of bleeding
you are anaemic (have low red blood cell count)
you are prone to infections
you have a history of seizures
you have liver or kidney problems, especially if you are on dialysis
you have diarrhoea

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

vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or narrowing of the visual field.
loss of sensation in arms or legs or tingling or prickling sensations in arms or legs.
during or after taking antibiotics, including Linezolid S.A.L.F., you develop diarrhoea. If diarrhoea becomes severe or persistent, or if you notice blood or mucus in your stools, stop taking Linezolid S.A.L.F. immediately and consult your doctor. In such cases, do not take medicines that stop or slow down intestinal movements.
recurrent nausea or vomiting, abdominal pain, or rapid breathing.
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.
feeling unwell with muscle weakness, headache, confusion, and memory problems, which may indicate hyponatraemia (low sodium levels in the blood).

Other medicines and Linezolid S.A.L.F.

There is a risk that Linezolid S.A.L.F. may interact with other medicines, causing unwanted effects such as changes in blood pressure, body temperature, or heart rate.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.
Inform your doctor if you are taking or have taken within the last 2 weeks the following medicines, as Linezolid S.A.L.F. must not be taken if you are currently taking or have recently taken these medicines (see also section 2 above “Do not take Linezolid S.A.L.F.”).

monoamine oxidase inhibitors (MAOIs), for example phenelzine, isocarboxazid, selegiline, moclobemide. These are medicines generally used to treat depression or Parkinson’s disease.

Also inform your doctor if you are taking any of the following medicines. Your doctor may still decide to administer Linezolid S.A.L.F., but will need to monitor your general health and blood pressure before and during treatment. In other cases, your doctor may decide that another treatment is better for you.

Decongestants, cold or flu remedies containing pseudoephedrine or phenylpropanolamine.
Certain medicines used to treat asthma, such as salbutamol, terbutaline, fenoterol.
Certain antidepressants such as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
Medicines used to treat migraine, such as sumatriptan and zolmitriptan.
Medicines used to treat severe and sudden allergic reactions, such as adrenaline (epinephrine).
Medicines that raise blood pressure, such as noradrenaline (norepinephrine), dopamine, and dobutamine.
Opioids, for example meperidine (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.

Linezolid S.A.L.F. with food, drinks and alcohol

Linezolid S.A.L.F. can be administered before, during, or after meals.
Avoid eating large amounts of aged cheeses, yeast extracts, or soybean products (e.g. soy sauce), and avoid drinking alcohol, especially draught beer and wine. This is because Linezolid S.A.L.F. may react with a substance called tyramine, naturally present in some foods. This interaction may cause an increase in blood pressure.
If you develop a throbbing headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding and fertility

The effect of Linezolid S.A.L.F. in pregnant women is unknown. Therefore, this medicine should not be taken during pregnancy unless clearly indicated by your doctor. If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
While taking Linezolid S.A.L.F., you must not breastfeed, as the medicine passes into breast milk and may affect the infant.

Driving and using machines

Linezolid S.A.L.F. may cause mild dizziness or vision problems. If this occurs, do not drive or operate machinery. Remember that your ability to drive or operate machinery may be impaired if you do not feel well.

Linezolid S.A.L.F. contains sodium

1 ml of Linezolid S.A.L.F. solution contains 3.9 mg of sodium (the main component of table salt), equivalent to 1.18 g of sodium in a 300 ml bag.
The recommended daily dose for adults, 2 bags of 300 ml, contains 2.36 g of sodium, equivalent to 118% of the maximum recommended daily dietary sodium intake for an adult.
Inform your doctor or nurse if you are on a low-sodium diet.

3. How to take Linezolid S.A.L.F.

Adults

Take this medicine exactly as stated in this leaflet or as instructed by your doctor, pharmacist, or nurse. If you have any doubts, consult your doctor, pharmacist, or nurse.
This medicine will be administered to you as a slow intravenous infusion (drip) by a doctor or healthcare professional. The recommended dose for adults (over 18 years of age) is 300 ml (600 mg of linezolid) twice daily, administered directly into the bloodstream via slow intravenous infusion over a period of 30 to 120 minutes.
If you are undergoing renal dialysis, take Linezolid S.A.L.F. after dialysis.
A treatment course usually lasts 10 to 14 days, but may last up to 28 days. The safety and efficacy of this medicine for periods longer than 28 days have not been established. Your doctor will decide the duration of treatment.
While taking Linezolid S.A.L.F., your doctor should perform regular blood tests to monitor your blood cell counts.
If you take Linezolid S.A.L.F. for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents

Linezolid S.A.L.F. is not normally used to treat children and adolescents (under 18 years of age).

If you take more Linezolid S.A.L.F. than you should

If you think you have been given too much Linezolid S.A.L.F., inform your doctor or nurse immediately.

If you forget to take Linezolid S.A.L.F.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Tell your doctor, nurse, or pharmacist immediately if you notice any of the following side effects during treatment with Linezolid S.A.L.F.:

Serious side effects (frequency indicated in parentheses) of Linezolid S.A.L.F. include:

severe skin reactions (uncommon), swelling, especially of the face and neck (uncommon), shortness of breath and/or difficulty breathing (rare). These may be signs of an allergic reaction, and treatment with Linezolid S.A.L.F. may need to be stopped. Skin reactions such as raised purple rash due to blood vessel inflammation (rare), skin ulceration and peeling (dermatitis) (uncommon), rash (common), itching (common).
vision disturbances (uncommon), such as blurred vision (uncommon), changes in colour vision (frequency not known), difficulty seeing details (frequency not known), or narrowing of the visual field (rare).
severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare cases may lead to life-threatening complications (uncommon).
recurrent nausea or vomiting, abdominal pain, or rapid breathing (rare).
seizures or convulsions have been reported with Linezolid S.A.L.F. (uncommon).
Serotonin syndrome (frequency not known): if you experience agitation, confusion, delirium, rigidity, tremor, lack of coordination, seizures, rapid heartbeat, severe breathing problems, and diarrhoea (suggestive of serotonin syndrome) while also taking antidepressant medicines called SSRIs or opioids (see section 2), inform your doctor.
unexplained bleeding or bruising, possibly due to changes in the number of certain blood cells that may affect clotting or lead to anaemia (common).
changes in the number of certain blood cells that may affect the ability to fight infections (uncommon); signs of infection may include: fever (common), sore throat (uncommon), mouth ulcers (uncommon), and fatigue (uncommon).
rhabdomyolysis (rare): 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-lived symptoms such as vision loss, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
ringing in the ears (tinnitus) (uncommon).

Numbness, tingling sensations, or blurred vision have been reported in patients treated with Linezolid S.A.L.F. for more than 28 days. If you have vision problems, consult your doctor as soon as possible.

Other side effects include:

Common (may affect up to 1 in 10 people):

Fungal infections, especially vaginal or oral candidiasis
Headache
Metallic taste in the mouth
Diarrhoea, nausea, or vomiting
Changes in certain blood test results, including values used to monitor proteins, salts, or enzymes measuring kidney or liver function, or blood sugar levels
Difficulty sleeping
Increased blood pressure
Anaemia (low red blood cell count)
Dizziness
Localised or general abdominal pain
Constipation
Indigestion
Localised pain
Reduced platelet count

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

Inflammation of the vagina or genital area in women
Sensations such as tingling or numbness
Swelling, pain, or discolouration of the tongue
Dry mouth
Pain at the infusion site
Inflammation of the veins (including at the infusion site)
Need to urinate more frequently
Chills
Feeling thirsty
Increased sweating
Hyponatraemia (low sodium levels in the blood)
Hypoglycaemia (low blood sugar levels)
Kidney failure
Abdominal distension
Injection site pain
Increased creatinine
Stomach ache
Changes in heart rate (e.g. increased heart rate)
Reduction in blood cell count
Weakness and/or sensory disturbances

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

Superficial tooth discoloration, removable with professional dental cleaning (manual removal)
Black, hairy appearance of the tongue surface

The following side effects have also been reported (frequency not known: frequency cannot be estimated from available data):

Alopecia (hair loss)

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Linezolid S.A.L.F.

Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the box, bags, and outer packaging after “EXP”.
The expiry date refers to the last day of that month.
Hospital staff must ensure that Linezolid S.A.L.F. infusion solution is not used after the expiry date printed on the bag and that it is administered immediately after opening. They must also perform a visual inspection of the solution before use and only use a clear solution free from particles. The staff will also ensure that the solution is stored correctly at a temperature not exceeding 25°C, in its original packaging and within the protective aluminium overbag, to protect it from light and keep it out of the sight and reach of children, for the required duration.

After opening:
From a microbiological standpoint, the product should be used immediately, except when the method of opening excludes the risk of contamination. If not used immediately, the time and conditions of storage are the responsibility of the user.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Linezolid S.A.L.F. contains

The active substance is linezolid. 1 ml of solution contains 2 mg of linezolid.
The other ingredients are sodium chloride, disodium citrate dihydrate, citric acid monohydrate, hydrochloric acid or sodium hydroxide (pH adjusters), and water for injections.

Description of the appearance of Linezolid S.A.L.F. and contents of the pack

Linezolid S.A.L.F. is a clear, colourless or slightly yellow infusion solution, supplied in single PP bags protected by aluminium overbags. Each bag contains 300 ml of solution (600 mg of linezolid).
Pack sizes: a box containing 20 bags or a box containing 15 bags.

Marketing Authorisation Holder

S.A.L.F. S.p.A. Laboratorio Farmacologico – Via Marconi, 2 – 24069 Cenate Sotto (BG) – Italy

Manufacturer

S.A.L.F. S.p.A. Laboratorio Farmacologico – Via Mazzini, 9 – 24069 Cenate Sotto (BG) – Italy

The following information is intended exclusively for doctors or healthcare professionals:

Linezolid S.A.L.F. 2mg/ml infusion solution
Linezolid
IMPORTANT: Refer to the Summary of Product Characteristics before prescribing.
Linezolid is not active against infections caused by Gram-negative pathogens. When co-infection with Gram-negative pathogens is suspected or confirmed, concomitant specific therapy against Gram-negative pathogens should be initiated.

Description
PVC-free single-use infusion bags, ready for use, protected by aluminium overbags. Each bag contains 300 ml of solution (600 mg of linezolid).
Pack sizes: a box containing 20 or 15 bags.
Linezolid S.A.L.F. 2mg/ml infusion solution contains linezolid 2mg/ml in an isotonic, clear solution ranging from colourless to yellow. Excipients: sodium chloride, disodium citrate dihydrate, anhydrous citric acid, hydrochloric acid or sodium hydroxide, water for injections.

Dosage and method of administration
Treatment with linezolid should only be initiated in a hospital setting and after consultation with a qualified specialist, such as a microbiologist or infectious disease specialist.
Patients starting treatment with the parenteral formulation may subsequently switch to oral formulations if clinically appropriate. In such cases, no dose adjustment is required, as the oral bioavailability of linezolid is approximately 100%.
The infusion solution must be administered over a period of 30 to 120 minutes.
The recommended dose of linezolid should be administered intravenously twice daily.

Recommended dosage and duration of treatment in adults
The duration of treatment depends on the pathogen, site and severity of infection, and the patient’s clinical response.
The following recommendations on treatment duration reflect those used in clinical trials. Shorter treatment regimens may be appropriate for certain types of infection but have not been evaluated in clinical trials.
The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for periods longer than 28 days have not been established.
No dose increase or extension of treatment duration is required for infections associated with concurrent bacteraemia.
The recommended dosage for infusion solution, tablets, and granules for oral suspension is identical and is as follows:

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

Paediatric population: The safety and efficacy of linezolid in children (< 18 years) have not been established. The data currently available are reported in sections 4.8, 5.1 and 5.2 of the SmPC, but no dosage recommendations can be made.
Elderly: no dose adjustment is required.
Renal impairment: no dose adjustment is required.
Severe renal impairment (i.e. creatinine clearance < 30 ml/min): no dose adjustment is required. Since the clinical significance of higher exposure (up to 10-fold) to the two main metabolites of linezolid in patients with severe renal impairment is unknown, linezolid should be used with particular caution in these patients and only when the expected benefit is considered to outweigh the theoretical risk.
Since approximately 30% of a 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 eliminated by haemodialysis, but concentrations of these metabolites remain substantially higher after dialysis compared to those observed in patients with normal renal function or mild to moderate renal impairment. Linezolid should therefore be used with particular caution in patients with severe renal impairment undergoing dialysis, and only when the expected benefit outweighs the theoretical risk.
There are currently no data on 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 (i.e. Child-Pugh class A or B): no dose adjustment is required.
Severe hepatic impairment (i.e. Child-Pugh class C): Since linezolid is metabolised via a non-enzymatic process, altered hepatic function is not expected to significantly affect its metabolism; therefore, no dose adjustment is recommended. However, clinical data are limited and the use of linezolid in such patients is recommended only when the expected benefits outweigh the theoretical risks (see sections 4.4 and 5.2).

Contraindications
Patients with hypersensitivity to linezolid or any of the excipients.
Linezolid must not be used in patients being treated with monoamine oxidase inhibitors (MAOIs) A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking such medicines.
Linezolid must not be administered to patients who have the following clinical conditions or who are taking the following concomitant medicines unless facilities for close patient observation and monitoring of blood pressure are available:
Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorders, or acute confusional states.
Patients taking the following medicines: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5HT1 receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasoactive substances (e.g. adrenaline, noradrenaline), dopaminergic agents (e.g. dopamine), dobutamine, pethidine or buspirone.
Breast-feeding must be discontinued before or during administration (see section 4.6 of the SmPC).

Special warnings and precautions for use
Myelosuppression
Cases of myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) have been reported in patients treated with linezolid. In cases with known outcome, haematological parameters returned towards pre-treatment values after discontinuation of linezolid. The risk of these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid may be at increased risk of haematological disorders compared to younger patients. Thrombocytopenia may occur more commonly in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate or severe hepatic impairment. Careful monitoring of blood cell counts is therefore recommended in patients with pre-existing anaemia, granulocytopenia or thrombocytopenia; in patients receiving concomitant medicinal products that may reduce haemoglobin levels, depress blood cell counts or exert adverse effects on platelet count or function; in patients with severe renal impairment or moderate to severe hepatic impairment; and in patients receiving linezolid for more than 10–14 days.
In such patients, linezolid should be administered only when close monitoring of haemoglobin levels or blood cell and platelet counts is possible.
If significant myelosuppression develops during treatment with linezolid, administration should be discontinued, except when continuation of therapy is considered absolutely necessary; in such cases, intensive monitoring of blood cell counts and appropriate therapeutic measures should be initiated.
Weekly full blood count monitoring (including haemoglobin levels, platelet count, and total and differential white blood cell count) is also recommended in patients receiving linezolid, regardless of baseline values.
In compassionate use studies, a higher incidence of severe anaemia has been reported in patients treated with linezolid for periods exceeding the recommended maximum duration of 28 days. In these patients, the need for blood transfusion was more frequent. Cases of anaemia requiring transfusion have also been reported in post-marketing experience, with a higher incidence in patients treated with linezolid for periods exceeding 28 days.
In post-marketing experience, cases of sideroblastic anaemia have been reported. In cases where onset time was known, most patients had received linezolid treatment for more than 28 days. Most patients showed complete or partial recovery after discontinuation of linezolid therapy, with or without treatment for anaemia.

Imbalance in mortality rate in a clinical study in patients with catheter-related Gram-positive bloodstream infections
In an open-label clinical study in critically ill patients with intravascular catheter-related infections, a higher mortality rate was observed in patients treated with linezolid compared to vancomycin, dicloxacillin or oxacillin [78/363 (21.5%) versus 58/363 (16.0%)]. The main factor influencing mortality rate was the baseline severity of Gram-positive infection. Mortality was similar in patients with infections caused exclusively by Gram-positive bacteria (odds ratio 0.96; 95% confidence interval: 0.58–1.59), but was significantly higher (p=0.0162) in the linezolid treatment group among patients who had any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38–4.46). The greatest difference occurred during treatment and within 7 days of stopping therapy. A higher number of patients in the linezolid treatment group developed Gram-negative infections during the study, and patients died from Gram-negative and polymicrobial infections. Therefore, in complicated skin and soft tissue infections, linezolid should be used in patients with confirmed or suspected concomitant Gram-negative pathogen infections only when no other therapeutic alternatives are available. In such circumstances, concomitant treatment against Gram-negative pathogens should be initiated simultaneously.

Antibiotic-associated diarrhoea and colitis
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. It is therefore important to consider this diagnosis in patients who develop severe diarrhoea during or after treatment with linezolid. If antibiotic-associated diarrhoea or colitis is suspected or confirmed, ongoing antibacterial therapy, including linezolid, should be discontinued and appropriate therapeutic measures initiated immediately. In this situation, antiperistaltic agents are contraindicated.

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

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. As a consequence of this inhibition, adverse events such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur; these events are more common when the medicinal product is used for more than 28 days.

Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with concomitant administration of linezolid and serotonergic medicinal products, including selective serotonin reuptake inhibitors (SSRIs) and opioids, have been reported (see section 4.5 of the SmPC). Concomitant administration of linezolid and serotonergic drugs is therefore contraindicated (see section 4.3 of the SmPC), except in cases where concomitant administration of linezolid and serotonergic medicinal products is essential. In such cases, patients must be closely monitored for signs and symptoms of serotonin syndrome, such as changes in cognitive function, hyperthermia, hyperreflexia and lack of coordination. If these signs and symptoms occur, the physician must consider discontinuing one or both concomitant treatments; if the serotonergic medicinal product is discontinued, withdrawal symptoms may occur.

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 are observed, linezolid should be discontinued and appropriate therapy initiated.

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

Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis, have been reported in patients receiving linezolid therapy, sometimes progressing to vision loss. These cases 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 disturbances, such as changes in visual acuity, changes in colour vision, blurred vision or visual field defects. In such cases, timely ophthalmological evaluation is recommended, and referral to an ophthalmologist if necessary. In cases of linezolid administration for periods exceeding the recommended maximum duration of 28 days, regular monitoring of visual function should be performed in all patients.
If peripheral or optic neuropathy develops, continuation of linezolid therapy in these patients should be evaluated considering the potential risks.
The risk of neuropathies may increase when linezolid is used in patients who are concomitantly taking or have recently taken antimycobacterial medicinal products for the treatment of tuberculosis.

Seizures
Seizures have been reported in patients treated with Linezolid S.A.L.F. In most cases, a positive history of seizures or risk factors for seizures was reported. In case of a positive history of seizures, patients should be advised to inform their physician.

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO); however, at doses used for antibacterial therapy, it does not exert an antidepressant effect. Very limited data are available from both pharmacological interaction studies and from the safety of linezolid administered to patients with pre-existing clinical conditions and/or concomitant therapies that may place them at risk due to MAO inhibition. The use of linezolid is therefore not recommended in these circumstances unless close patient monitoring and surveillance are possible.

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

Superinfections
Clinical studies have not evaluated the effects of linezolid therapy on normal flora.
The use of antibiotics may occasionally lead to overgrowth of non-susceptible microorganisms. For example, approximately 3% of patients treated with the recommended dose of linezolid developed drug-related candidiasis during clinical studies. Appropriate measures should be taken if superinfection occurs during therapy.

Special populations
Linezolid should be used with particular caution in patients with severe renal impairment and only when the expected benefit outweighs the theoretical risk (see sections 4.2 and 5.2 of the SmPC).
Linezolid is recommended to be administered in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk.

Fertility
Linezolid reversibly reduced fertility and induced morphological abnormalities in sperm of adult male rats at exposure levels equivalent to those expected in humans; possible effects of linezolid on the male reproductive system in humans are unknown.

Clinical studies
The safety and efficacy of linezolid administered for periods exceeding 28 days have not been established.
Controlled studies 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 such lesions is limited.

Excipients
1 ml of Linezolid S.A.L.F. solution contains 3.9 mg of sodium, corresponding to 1.18 g of sodium in a 300 ml bag. The daily dose of 2 bags of 300 ml contains 2.36 g of sodium, equivalent to 118% of the maximum recommended daily intake (RDI) from diet for adults as defined by the WHO, which corresponds to 2 g of sodium. The sodium content should be taken into account in patients on a sodium-controlled diet.
Linezolid S.A.L.F. infusion solution may be further prepared for administration with solutions containing sodium (see sections 4.2, 6.2 and 6.6), and this should be taken into consideration with regard to the total amount of sodium from all sources to be administered to the patient.

Interactions
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). Very limited data are available from both pharmacological interaction studies and from the safety of linezolid administered to patients receiving concomitant therapy with medicinal products that may pose a risk due to MAO inhibition. The use of linezolid is therefore not recommended in these circumstances unless close monitoring and careful surveillance of the recipient are possible.

Potential interactions causing increases in blood pressure
In healthy normotensive volunteers, linezolid potentiated the blood pressure increase induced by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine and phenylpropanolamine resulted in mean increases in systolic blood pressure of 30–40 mmHg, compared to increases of 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 subjects. Careful titration of the dosage of vasoactive medicinal products, including dopaminergic agents, is recommended to achieve the desired response when administered concomitantly with linezolid.

Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects received dextromethorphan (two 20 mg doses 4 hours apart), with or without linezolid. In normal subjects treated with linezolid and dextromethorphan, no effects of serotonin syndrome (confusion, delirium, restlessness, tremor, erythema, diaphoresis and hyperthermia) were observed.
Post-marketing experience: a report has been documented of a patient who developed symptoms similar to serotonin syndrome during concomitant use of linezolid and dextromethorphan, which resolved upon discontinuation of both treatments.
In clinical experience with concomitant use of linezolid and serotonergic medicinal products, including selective serotonin reuptake inhibitors (SSRIs) and opioids, cases of serotonin syndrome have been reported. Concomitant administration is therefore contraindicated (see section 4.3 of the SmPC), but management of patients for whom treatment with linezolid and serotonergic medicinal products is essential is described in the section Special warnings and precautions for use.

Use with tyramine-rich foods
Subjects treated with linezolid and less than 100 mg of tyramine did not show any significant pressor response. This indicates that only excessive intake of foods and beverages with high tyramine content should be avoided (e.g. aged cheese, yeast extracts, undistilled alcoholic beverages and fermented soy products such as soy sauce).

Medicinal products metabolised by cytochrome P450
Linezolid is not significantly metabolised by the cytochrome P450 (CYP) enzyme system and does not inhibit any of the clinically significant isoforms of human CYP (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-mediated pharmacological interaction with linezolid is expected.

Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers who received linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg 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 significance are unknown.

Warfarin
When warfarin was co-administered with linezolid under steady-state conditions, a 10% reduction in mean maximum INR (International Normalized Ratio) was observed during concomitant administration, with a 5% reduction in INR AUC. The clinical significance of these findings, if any, cannot be determined due to insufficient data from patients treated with warfarin and linezolid.

Fertility, pregnancy and lactation
Pregnancy
Limited data are available on the use of linezolid in pregnant women. Animal studies have shown toxic effects on reproduction. A potential risk for humans exists.
Linezolid S.A.L.F. must not be used during pregnancy unless strictly necessary, i.e. only when the expected benefits outweigh the theoretical risk.

Lactation
Animal data indicate that linezolid and its metabolites may pass into breast milk and, consequently, breast-feeding must be discontinued before and during administration.

Fertility
In animal studies, linezolid caused a reduction in fertility.

Effects on ability to drive and use machines
Patients should be informed of the potential occurrence of dizziness or visual impairment symptoms during treatment with Linezolid S.A.L.F., and should therefore be advised not to drive or operate machinery if any of these symptoms occur.

Undesirable effects
The table below lists adverse reactions by frequency based on all randomized data from clinical studies involving over 6,000 adult patients treated for up to 28 days with the recommended doses of linezolid. The most commonly reported were diarrhoea (8.9%), nausea (6.9%), vomiting (4.3%) and headache (4.2%).
The most commonly reported drug-related adverse events leading to treatment discontinuation were headache, diarrhoea, nausea and vomiting. Approximately 3% of patients discontinued treatment due to a drug-related adverse event.
Additional adverse reactions reported during post-marketing experience are included in the table under the category “not known”, as the actual frequency cannot be calculated from the available data.
The following undesirable effects have been observed and reported during treatment with linezolid at the following frequencies: Very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).

System Organ Class	Common (≥1/100 and <1/10)	Uncommon (≥1/1,000 and <1/100)	Rare (≥1/10,000 and <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Infections and infestations	candidiasis, oral candidiasis, vaginal candidiasis, fungal infections	antibiotic-associated colitis, including 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, taste disturbance (metallic taste), dizziness	seizures, peripheral neuropathy, hypoesthesia, paresthesia			serotonin syndrome**
Eye disorders		optic neuropathy, blurred vision	changes in visual field defect*		optic neuritis, vision loss, visual acuity alterations, color vision alterations
Ear and labyrinth disorders	Common (≥1/100 and <1/10)	Uncommon (≥1/1,000 and <1/100) tinnitus	Rare (≥1/10,000 and <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Cardiac disorders		arrhythmia (tachycardia)
Vascular disorders	hypertension	transient ischemic attacks, phlebitis, thrombophlebitis
Gastrointestinal disorders	diarrhea, nausea, vomiting, localized or general abdominal pain, constipation, dyspepsia	pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, loose stools, stomatitis, tongue discoloration or disorders	superficial tooth discoloration
Hepatobiliary disorders	liver function test abnormalities; increase in AST, ALT or alkaline phosphatase	increase in total bilirubin
Skin and subcutaneous tissue disorders	pruritus, rash	angioedema, urticaria, bullous dermatitis, diaphoresis	toxic epidermal necrolysis#, Stevens-Johnson syndrome#, hypersensitivity vasculitis		alopecia
Renal and urinary disorders	increased blood urea	renal failure, increased creatinine, polyuria
Reproductive system and breast disorders		vulvovaginal disorders
System Organ Class	Common (≥1/100 and <1/10)	Uncommon (≥1/1,000 and <1/100)	Rare (≥1/10,000 and <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
General disorders and administration site conditions	fever, localized pain	chills, fatigue, injection site pain, increased thirst
Investigations	Biochemistry: Increased LDH, creatine kinase, lipase, non-fasting glucose. Decreased total proteins, albumin, sodium or calcium. Increased or decreased potassium or bicarbonate. Hematology: Increased neutrophils or eosinophils. Decreased hemoglobin, hematocrit or red blood cells. Increased or decreased platelets or white blood cells	Biochemistry: Increased sodium or calcium. Decreased non-fasting glucose. Increased or decreased chloride. Hematology: Increased reticulocytes. Decreased neutrophils.

See section Special warnings and precautions for use
** See sections Contraindications and Interactions

Estimated ADR frequency using the "Rule of 3"

† See information below
The following adverse reactions to linezolid have been considered severe in rare cases: localized abdominal pain,
transient ischaemic attacks and hypertension.
†In controlled clinical studies in which linezolid was administered for up to 28 days of treatment, reported cases of
anaemia were 2.0% of patients. During a compassionate use programme in patients with potentially fatal infections and concomitant underlying conditions, the percentage of patients who developed anaemia during treatment with linezolid for ≤ 28 days was 2.5% (33/1,326), compared to 12.3% (53/430) in cases where therapy lasted >28 days. The percentage of cases in which severe drug-related anaemia requiring blood transfusion was reported was 9% (3/33) in patients treated for ≤ 28 days and 15% (8/53) in those treated for >28 days.
Paediatric population
Safety data from clinical studies conducted in over 500 paediatric patients (from birth up to 17 years of age) do not indicate that the safety profile of linezolid in paediatric patients differs from that in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important, as it allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
Overdose
No specific antidote is known.
Cases of overdose have not been reported. However, the following information may be useful:
supportive treatment should be administered together with maintenance of glomerular filtration. Approximately 30% of a dose of linezolid is removed during 3 hours of haemodialysis, but no data are available on the elimination of linezolid by peritoneal dialysis or haemoperfusion.
Instructions for use and handling
For single use only. Remove the overwrap only at the time of use, then check for leaks by firmly squeezing the bag. If leakage is observed, discard the bag, as sterility may be compromised. The solution should be inspected visually prior to use and only clear, particle-free solutions should be used. Do not use these bags in series connections. Any unused solution should be discarded. Do not reconnect partially used bags.
Linezolid S.A.L.F. infusion solution is compatible with the following solutions: glucose 5% for intravenous infusion, sodium chloride 0.9% for intravenous infusion, Ringer's lactate solution for injection (Hartmann's solution for injection).
Incompatibilities
No additives should be added to this solution. If linezolid is to be administered in combination with another medicinal product, each medicinal product should be administered separately in accordance with their respective instructions for use. Similarly, if the same intravenous line is used for sequential infusion of different medicinal products, the line should be flushed with a compatible infusion solution before and after administration of linezolid.
Linezolid S.A.L.F. infusion solution is physically incompatible with the following substances: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin and sulfamethoxazole/trimethoprim. In addition, it is chemically incompatible with ceftriaxone sodium.
Shelf life
Before opening: 2 years
After opening: From a microbiological standpoint, the product should be used immediately, unless the method of opening excludes the risk of contamination. If not used immediately, the times and conditions of storage are the responsibility of the user.
Special precautions for storage
Do not store above 25°C.
Keep in the original packaging (overwrap and carton) until the time of use.