Linezolid polpharma

Package leaflet: Information for the user

Linezolid Polpharma, 2 mg/ml, infusion solution
Linezolidum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or nurse.
• This medicine has been prescribed for a specific patient only. Do not pass it on to others. It may harm other people, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of the leaflet

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

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

Linezolid Polpharma is an antibiotic belonging to the oxazolidinone group. It works by
inhibiting the growth of certain bacteria (microorganisms) that cause infections.
This medicine is used in adults to treat pneumonia and certain skin or soft tissue infections.
Your doctor will decide whether linezolid is appropriate for treating the specific infection you have.

2. Important information before using Linezolid Polpharma

When not to use Linezolid Polpharma

• If the patient is allergic to linezolid or any of the other ingredients of this medicine (listed in section 6).
• If the patient is currently taking or has taken within the last 2 weeks any medicines known as monoamine oxidase inhibitors (MAOIs), such as phenelzine, isocarboxazid, selegiline, or moklobemide. These medicines may be used in the treatment of depression or Parkinson's disease.
• If the patient is breastfeeding. Linezolid passes into breast milk and may harm the baby.

If the patient answers "yes" to any of the questions below, Linezolid Polpharma may not be suitable for them.
In such a case, the patient should inform their doctor, who may recommend performing general examinations and blood pressure monitoring before and during treatment, or decide to use an alternative, more appropriate treatment.
If there is any uncertainty whether the situations described below apply to the patient, consult a doctor.

• Does the patient have high blood pressure and is taking medication for it?
• Has hyperthyroidism been diagnosed in the patient?
• Does the patient have a tumour of the adrenal gland (pheochromocytoma) or carcinoid syndrome (caused by a tumour of the endocrine system, with symptoms such as diarrhoea, hot flushes, wheezing)?
• Does the patient suffer from bipolar depression, schizoaffective disorders, disorientation, or other psychiatric disorders?
• Is the patient taking any opioid medicines?
• Is the patient taking any of the following medicines:
• decongestants used for colds or flu containing pseudoephedrine or phenylpropanolamine,
• medicines used to treat asthma, e.g. salbutamol, terbutaline, fenoterol,
• antidepressants known as tricyclic antidepressants or SSRIs (selective serotonin reuptake inhibitors), e.g. amitriptyline, cypramine, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline,
• medicines used to treat migraine, e.g. sumatriptan and zolmitriptan,
• medicines used to treat severe allergic reactions, e.g. adrenaline (epinephrine),
• medicines that increase blood pressure, e.g. noradrenaline (norepinephrine), dopamine, and dobutamine,
• opioids, e.g. pethidine – used for moderate or severe pain,
• medicines used to treat anxiety disorders, e.g. buspirone,
• an antibiotic called rifampicin.

Concurrent use of certain medicines, including antidepressants and opioids, with Linezolid Polpharma may lead to serotonin syndrome – a potentially life-threatening condition (see section 2 "Linezolid Polpharma and other medicines" and section 4).
Warnings and precautions
If the patient has any of the following conditions, inform the doctor before starting treatment:

• tendency to bruising and bleeding,
• anaemia,
• susceptibility to infections,
• history of seizures,
• liver or kidney problems, especially if the patient is on dialysis,
• diarrhoea.

Inform the doctor immediately if any of the following occur during treatment:

• visual disturbances, such as blurred vision, changes in colour vision, difficulty seeing details, or narrowing of the visual field;
• loss of sensation in hands or feet, or tingling or prickling sensations;
• diarrhoea, which may occur during or after antibiotic treatment, including Linezolid Polpharma; if diarrhoea is severe or persistent, or if blood or mucus is visible in the stool, stop taking Linezolid Polpharma immediately and contact a doctor; in such cases, do not take medicines that stop or slow down intestinal motility.
• recurrent nausea or vomiting, abdominal pain, or increased breathing rate.

Linezolid Polpharma and other medicines
Linezolid Polpharma may sometimes interact with certain other medicines, potentially causing adverse effects such as changes in blood pressure, body temperature, or heart rate.
If the patient has taken any of the following medicines within the last 2 weeks, inform the doctor, as concomitant use is contraindicated in such cases (see also section 2 "When not to use Linezolid Polpharma"):

• monoamine oxidase inhibitors (MAOIs), e.g. phenelzine, isocarboxazid, selegiline, moklobemide. These medicines are used in the treatment of depression or Parkinson's disease.

Also inform the doctor if the patient is taking any of the following medicines. The doctor may decide to proceed with Linezolid Polpharma treatment but will need to monitor the patient's general health condition and blood pressure before and during treatment. Otherwise, the doctor may decide that alternative treatment is more suitable for the patient.

• Decongestants used for colds and flu containing pseudoephedrine or phenylpropanolamine.
• Certain medicines used to treat asthma, e.g. salbutamol, terbutaline, fenoterol.
• Certain antidepressants, known as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). There are many such medicines, including amitriptyline, cypramine, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• Medicines used to treat migraine, e.g. sumatriptan and zolmitriptan.
• Medicines used to treat acute, severe allergic reactions, e.g. adrenaline (epinephrine).
• Medicines that increase blood pressure, e.g. noradrenaline (norepinephrine), dopamine, and dobutamine.
• Opioids, e.g. pethidine – used to treat moderate or severe pain.
• Medicines used to treat anxiety disorders, e.g. buspirone.
• Anticoagulants, e.g. warfarin.

Tell the doctor about all medicines currently or recently taken by the patient, as well as any medicines the patient plans to take.
Linezolid Polpharma with food, drink, and alcohol

• Avoid consuming large amounts of mature cheeses, yeast extracts, soy products (e.g. soy sauce), and drinking alcohol, especially draught beer and wine. The medicine may interact with a substance called tyramine, naturally present in certain foods, leading to increased blood pressure.
• If the patient experiences a throbbing headache after eating or drinking, inform the doctor or pharmacist immediately.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to become pregnant, she should consult a doctor before using this medicine.
The effect of Linezolid Polpharma in pregnant women is unknown. Therefore, this medicine should not be used during pregnancy unless prescribed by a doctor.
Breastfeeding must be avoided while taking Linezolid Polpharma, as it passes into breast milk and may affect the baby.
Driving and operating machinery
Linezolid Polpharma may cause dizziness or visual disturbances. If these symptoms occur, the patient should not drive or operate machinery. Keep in mind that feeling unwell may impair the ability to drive or operate machinery.
Linezolid Polpharma contains:
Glucose
The medicine contains 13.7 g of glucose in 300 ml of solution (45.7 mg/ml). This should be taken into account in patients with diabetes.
Sodium
The medicine contains 113 mg of sodium (main component of table salt) in 300 ml of solution. This corresponds to 5.65% of the maximum recommended daily intake of sodium in the adult diet. This should be considered in patients on a sodium-restricted diet. The sodium content from the diluent should be included when calculating the total sodium content in the prepared diluted medicine. For precise information on the sodium content of the solution used to dilute the medicine, refer to the Summary of Product Characteristics.

3. How to use Linezolid Polpharma

Linezolid can be administered before, during, or after a meal.
Adults
The medicine will be given as an intravenous infusion (drip) by a doctor or healthcare professional.
The usual dose for adult patients (aged 18 years and older) is 300 ml of solution (600 mg of linezolid) administered twice daily directly into the bloodstream (intravenously) via infusion over 30 to 120 minutes.
If the patient is undergoing dialysis, Linezolid Polpharma should be administered after completion of the dialysis session.
Treatment usually lasts from 10 to 14 days, but may last up to 28 days. The efficacy and safety of using this medicine for longer than 28 days have not been established. The duration of treatment will be determined by the physician.
During treatment with Linezolid Polpharma, your doctor will recommend regular blood tests to monitor blood counts.
If you are treated with Linezolid Polpharma for longer than 28 days, your doctor should recommend an eye examination.
Use in children and adolescents
Linezolid Polpharma is generally not recommended for use in children and adolescents (under 18 years of age).
Use of a higher than recommended dose of Linezolid Polpharma
If you suspect that you have received too high a dose of Linezolid Polpharma, inform your doctor or nurse immediately.
Missed dose of Linezolid Polpharma
The medicine is administered under strict supervision, so it is unlikely that a dose will be missed. However, if you think a dose has been missed, inform your doctor or nurse immediately.
If you have any further questions about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
If any of the side effects listed below occur, you must immediately
tell your doctor, nurse or pharmacist:

• skin reactions such as redness, pain or peeling of the skin (skin inflammation), rash, itching or swelling, particularly around the face and neck; these may be symptoms of an allergic reaction and it may be necessary to stop treatment with Linezolid Polpharma;
• vision problems such as changes in visual acuity, changes in colour vision, difficulty in seeing details or narrowing of the visual field;
• severe diarrhoea with blood and (or) mucus (inflammation of the intestine, including antibiotic-associated pseudomembranous colitis), which rarely may lead to life-threatening complications;
• recurrent nausea or vomiting, abdominal pain or rapid breathing;
• seizures or epileptic fits have been reported during treatment;
• serotonin syndrome (frequency unknown) - if the patient develops excessive agitation, confusion, hallucinations, rigidity, tremor, lack of coordination, seizures, rapid heartbeat, severe breathing problems and diarrhoea (suggesting serotonin syndrome), especially when taking antidepressant medicines known as SSRIs or opioids, tell your doctor (see section 2).

In patients treated with the medicine for longer than 28 days, numbness,
tingling or blurred vision have been reported. If the patient experiences any visual disturbances, they should contact their doctor as soon as possible.
Other side effects
Common (occurring in not more than 1 in 10 patients):

• fungal infections, especially of the vagina or oral thrush
• headache
• metallic taste in the mouth
• diarrhoea, nausea or vomiting
• changes in results of certain blood tests, including kidney or liver function tests or increased blood sugar levels
• bleeding or bruising of unknown cause, which may be due to changes in the number of certain types of blood cells, which in turn may affect blood clotting and lead to anaemia
• sleep disturbances
• increased blood pressure
• anaemia (low number of red blood cells)
• changes in the number of certain blood cells, which may affect the ability to fight infections
• skin rash
• itching of the skin
• dizziness
• local or generalised abdominal pain
• constipation
• indigestion
• localised pain
• fever.

Uncommon (occurring in not more than 1 in 100 patients):

• inflammation of the vagina or genital area in women
• sensory disturbances such as tingling or numbness
• blurred vision
• ringing in the ears (tinnitus)
• phlebitis
• dryness or pain in the mouth, swelling, irritation or discolouration of the tongue
• pain at or around the site of infusion
• inflammation of veins (including the vein used for infusion)
• need to pass urine more frequently
• chills
• feeling tired or thirsty
• pancreatitis
• increased sweating
• changes in blood levels of proteins and salts or enzyme activity indicating kidney or liver function
• seizures
• hyponatraemia (low sodium levels in the blood)
• kidney function disorders
• decrease in platelet count
• bloating
• transient ischaemic attacks (transient disturbances in blood supply to the brain causing temporary symptoms such as loss of vision, weakness of upper and lower limbs, slurred speech and loss of consciousness)
• pain at the injection site
• skin inflammation
• increased creatinine levels
• abdominal pain
• changes in heart rhythm (e.g. increased rate).

Rare (occurring in not more than 1 in 1000 patients):

• narrowing of the visual field
• superficial discolouration of teeth, reversible after dental cleaning (manual removal of tartar).

The following side effects have also been reported
Frequency unknown (cannot be estimated from the available data):

• serotonin syndrome (symptoms include rapid heartbeat, disorientation, profuse sweating, hallucinations, involuntary movements, chills and tremors)
• lactic acidosis (symptoms include recurrent nausea and vomiting, abdominal pain, rapid breathing)
• severe skin reactions
• sideroblastic anaemia (a type of anaemia (low number of red blood cells))
• hair loss
• colour vision disturbances, difficulty in perceiving details
• decrease in blood cell count
• weakness and (or) sensory disturbances.

Reporting of side effects
If you experience any side effects, including any not listed in this leaflet, tell your doctor or nurse. Side effects can also be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorisation holder.
Reporting side effects helps provide more information on the safety of this medicine.

5. How to store Linezolid Polpharma

Hospital staff will ensure that the expiry date indicated on the Linezolid Polpharma label has not been exceeded and that the medicine is administered to the patient immediately after opening. Before administration, it will be verified that the solution is clear, as it should only be administered if it is free from particulate matter. It will also be checked whether the solution is stored correctly, in its outer packaging, to protect it from light.
The marking on the packaging following "EXP" indicates the expiry date, and that following "Lot" indicates the batch number.
The medicine should be stored out of sight and reach of children.

6. Contents of the pack and other information

What Linezolid Polpharma contains

• The active substance is linezolid. One ml of solution contains 2 mg of linezolid.
• The other ingredients are: monohydrate glucose (a type of sugar), disodium citrate dihydrate (E331), anhydrous citric acid (E330), hydrochloric acid 0.1 N (for pH adjustment), sodium hydroxide 0.1 N (for pH adjustment), and water for injections.

What Linezolid Polpharma looks like and contents of the pack
Linezolid Polpharma is a clear, colourless to yellow solution.
The medicine is packed in single-use bags made of low-density polyethylene (LDPE),
formed with an Insocap-type adapter, containing 300 ml of solution (600 mg linezolid).
Each cardboard box contains 1 or 10 polyethylene bags.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Zakłady Farmaceutyczne POLPHARMA S.A.
ul. Pelplińska 19, 83-200 Starogard Gdański
tel. + 48 22 364 61 01

Information intended exclusively for healthcare professionals

IMPORTANT. The product should be prescribed only after reviewing the Summary of Product Characteristics.
Linezolid Polpharma, 2 mg/ml, infusion solution, is an isotonic, clear, colorless to yellow solution. One ml contains 2 mg of linezolid. Other ingredients: glucose monohydrate, disodium citrate dihydrate (E331), anhydrous citric acid (E330), hydrochloric acid 0.1 N (for pH adjustment), sodium hydroxide 0.1 N (for pH adjustment), water for injections.
Linezolid is not effective in the treatment of infections caused by Gram-negative bacteria. If an infection caused by Gram-negative bacteria is confirmed or suspected, appropriate concomitant therapy against these bacteria must be initiated.

Dosage and method of administration
Treatment with linezolid should be initiated only in hospital settings and after consultation with a specialist in microbiology or infectious diseases.
In patients who started treatment with the parenteral formulation, a switch to the oral formulation may be made if clinically indicated. There is no need to modify the dosage, as the oral bioavailability of linezolid is approximately 100%.
The infusion solution should be administered by infusion over 30 to 120 minutes.
The recommended dose of linezolid should be administered iv or orally twice daily.

Recommended dosage and duration of treatment in adults
The duration of treatment depends on the type of pathogenic microorganism, site and severity of infection, and the patient's clinical response to treatment.
The treatment duration recommendations presented below are consistent with those used in clinical trials. In certain types of infections, a shorter treatment duration may be sufficient; however, clinical trial data on such shorter regimens are lacking.
The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been established.
In infections with concomitant bacteremia, there is no need to increase the dose or prolong the duration of treatment.
Dosage recommendations for the intravenous infusion solution and tablets are identical and are as follows:

Children and adolescents
There are insufficient data on the safety and efficacy of linezolid in children and adolescents (aged <18 years) to establish a recommended dosage. Therefore, linezolid is not recommended in this age group until further data become available.

Elderly patients
No dose adjustment is necessary.

Patients with renal impairment
No dose adjustment is necessary.
Patients with severe renal impairment (i.e. creatinine clearance <30 ml/min)
No dose adjustment is necessary. Due to the uncertain clinical significance of increased exposure (up to 10-fold) to the two major metabolites of linezolid in patients with severe renal impairment, linezolid should be used with particular caution and only in patients for whom the anticipated benefit outweighs the theoretical risk.
Since approximately 30% of a dose of linezolid is removed from the body during a 3-hour hemodialysis session, linezolid should be administered after dialysis in patients undergoing dialysis. Hemodialysis also leads to partial removal of the main metabolites of linezolid from the body; however, their concentrations remain significantly higher after dialysis than those observed in patients with normal or mild to moderate renal impairment.
Therefore, in patients with severe renal impairment undergoing dialysis, linezolid should be used with particular caution and only when the anticipated benefit outweighs the theoretical risk.
To date, there are no data on the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or other alternative treatments for renal failure (other than hemodialysis).

Patients with hepatic impairment
In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), no dose adjustment is necessary.
Patients with severe hepatic impairment (i.e. Child-Pugh class C)
Linezolid is metabolized via non-enzymatic processes; therefore, it can be expected that liver dysfunction will not significantly affect the metabolism of this drug. However, there are no pharmacokinetic data, and clinical data on the use of linezolid in patients with severe hepatic impairment are limited. Linezolid should be used with particular caution in patients with severe hepatic impairment and only when the anticipated benefit outweighs the theoretical risk.

Contraindications
Hypersensitivity to linezolid or to any of the excipients of this product.
Linezolid must not be used in patients who are concurrently receiving any monoamine oxidase inhibitors type A or B (e.g. phenelzine, isocarboxazid, selegiline, moklobemide) or within two weeks after discontinuation of such treatment.
Linezolid should not be administered to patients with the underlying conditions listed below or who are concurrently receiving the types of medications listed below, unless close monitoring of the patient and blood pressure monitoring are possible.

• Patients with untreated hypertension, pheochromocytoma, carcinoid tumour, hyperthyroidism, bipolar depression, schizoaffective disorders, acute states of disorientation.
• Patients receiving any of the following medications: serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT receptor agonists (triptans), drugs with direct or indirect sympathomimetic action (including bronchodilators, pseudoephedrine and phenylpropanolamine), pressor amines (e.g. adrenaline, noradrenaline), dopaminergic agents (e.g. dopamine, dobutamine), meperidine or buspirone.

Breastfeeding must be discontinued prior to initiating treatment and not resumed during treatment.

Special warnings and precautions for use
Bone marrow suppression
Bone marrow suppression (including anaemia, leukopenia, pancytopenia and thrombocytopenia) has been observed in patients treated with linezolid. In cases where treatment outcomes were known, abnormal blood test results returned to pre-treatment values after discontinuation of linezolid. The risk of such events appears to be related to the duration of therapy. Elderly patients treated with linezolid have a higher risk of blood count disorders than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal impairment, regardless of dialysis. Therefore, blood counts should be closely monitored in patients with pre-existing anaemia, granulocytopenia or thrombocytopenia, in patients concurrently receiving drugs that may reduce haemoglobin levels, blood cell counts or affect platelet count or function, in patients with severe renal impairment, and in patients receiving linezolid for longer than 10 to 14 days. Linezolid may be administered to these patients only if close monitoring of haemoglobin concentration, blood cell counts and platelet counts is possible.
If significant bone marrow suppression occurs during treatment with linezolid, treatment should be discontinued unless continuation is absolutely necessary. In such cases, blood parameters should be monitored particularly carefully and appropriate measures initiated.
Furthermore, weekly monitoring of peripheral blood count (including haemoglobin concentration, platelet count and white blood cell count with differential) is recommended in all patients receiving linezolid, regardless of initial blood count results.
In studies involving the use of linezolid for humanitarian reasons before marketing authorization, an increased incidence of severe anaemia was observed in patients who received linezolid for longer than the maximum recommended 28 days. These patients required more frequent blood transfusions. Cases of anaemia requiring blood transfusion have also been reported after marketing authorization, more frequently after use of the drug for more than 28 days.
After marketing authorization, cases of sideroblastic anaemia have been reported. Most patients in whom initial symptoms were observed had been treated with linezolid for longer than 28 days. After discontinuation of linezolid, anaemia resolved completely or partially in most patients.

Variable mortality in a clinical trial in patients with Gram-positive bloodstream infections associated with intravascular catheters
In an open clinical trial in critically ill patients with catheter-related infections, higher mortality was observed in patients receiving linezolid compared to those treated with vancomycin, dicloxacillin or oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing mortality was the presence of Gram-positive bacterial infection at the start of treatment. Mortality rates were similar in patients with infection caused exclusively by Gram-positive bacteria (odds ratio 0.96; 95% confidence interval: 0.58–1.59), but were significantly higher (p=0.0162) in the group of patients receiving linezolid 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 after its completion. During the study, more patients in the linezolid group acquired Gram-negative microorganism infections and died from infections caused by Gram-negative bacteria and mixed infections.
Therefore, in complicated skin and soft tissue infections, linezolid may be used in patients with confirmed or suspected concurrent Gram-negative bacterial infection only when no other treatment options are available. In such cases, concomitant therapy against Gram-negative bacteria should be initiated without delay.

Diarrhoea and antibiotic-associated colitis
Pseudomembranous colitis has been reported during treatment with nearly every antibacterial agent, including linezolid. It is therefore important to consider this diagnosis in any patient who develops diarrhoea following administration of any antibacterial agent. If pseudomembranous colitis associated with antibiotic use is suspected or confirmed, discontinuation of linezolid therapy may be necessary. Appropriate management should be initiated.
During treatment with nearly every antibacterial agent, including linezolid, pseudomembranous colitis and Clostridium difficile-associated diarrhoea have been reported. This may range from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop acute diarrhoea after administration of linezolid. If diarrhoea or colitis is suspected or confirmed to be associated with antibiotic use, discontinuation of the antibacterial agent, including linezolid, is recommended, and appropriate treatment should be initiated promptly. In such situations, drugs inhibiting intestinal peristalsis are contraindicated.

Lactic acidosis
Lactic acidosis has been reported during treatment with linezolid. In patients who develop subjective and objective symptoms of metabolic acidosis during linezolid treatment, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels or hyperventilation, immediate medical intervention is required. If lactic acidosis occurs, the benefit-risk ratio should be evaluated before continuing linezolid treatment.

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. As a result, adverse effects such as metabolic acidosis, anaemia and neuropathy (optic or peripheral) may occur; these effects occur more frequently when the product is used for longer than 28 days.

Serotonin syndrome
Serotonin syndrome has been reported in spontaneous reports associated with concomitant use of linezolid and medicinal products with serotonergic activity, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, concomitant use of linezolid with serotonergic drugs is contraindicated, except when concomitant administration of linezolid and a serotonergic drug is necessary. In such cases, patients should be closely monitored for subjective and objective symptoms of serotonin syndrome, such as cognitive disturbances, very high fever, hyperreflexia and lack of coordination. If objective or subjective symptoms occur, the physician should consider discontinuing one or both drugs; withdrawal symptoms may occur after discontinuation of serotonergic drugs.

Peripheral neuropathy and optic neuropathy
Cases of peripheral neuropathy and optic neuropathy, sometimes progressing to vision loss, have been reported in patients treated with linezolid; these reports primarily involved patients treated for longer than the maximum recommended 28 days.
Patients should be advised to report symptoms of worsening vision, such as changes in visual acuity, changes in colour vision, blurred vision or visual field defects. In such cases, prompt referral for ophthalmological examination is recommended. If a patient uses Linezolid Polpharma for longer than the maximum recommended 28 days, regular monitoring of visual function should be performed.
If peripheral neuropathy or optic neuropathy occurs, continuation of treatment with Linezolid Polpharma should be considered based on risk assessment.
Increased risk of neuropathy may occur when linezolid is administered to patients who are currently or recently treated for tuberculosis with antituberculosis drugs.

Seizures
Seizures have been reported in patients treated with linezolid. Most of these patients had a history of seizures or risk factors. The physician should ask the patient about any history of seizures.

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI); however, at doses used in the treatment of infections, it does not have antidepressant activity. There are only very limited data from drug interaction and safety studies on the use of linezolid in patients with other diseases and (or) who are concurrently receiving drugs that may inhibit MAO. Therefore, linezolid should not be used in such situations unless close monitoring and patient control are possible.

Use with tyramine-rich foods
Patients should be advised that during treatment with linezolid, consumption of tyramine-rich foods should be limited.

Superinfections
The effect of linezolid on the physiological bacterial flora has not been evaluated in clinical trials.
Antibiotic use may occasionally lead to overgrowth of microorganisms not susceptible to the drug. For example, during a clinical trial, drug-dependent candidiasis occurred in approximately 3% of patients receiving recommended doses of linezolid. If superinfection occurs during treatment with linezolid, appropriate treatment should be initiated.

Special patient groups
Linezolid should be used with particular caution in patients with severe renal impairment and only when the anticipated benefit outweighs the theoretical risk.
Linezolid should be used in patients with severe hepatic impairment only when the anticipated benefit outweighs the theoretical risk.

Clinical trials
The safety and efficacy of linezolid administered for longer than 28 days have not been established. Controlled clinical trials have not been conducted in patients with diabetic foot, pressure ulcers, ischaemia-related lesions, severe burns or gangrene. Therefore, experience with the use of linezolid in such cases is limited.

Excipients
Glucose
This medicinal product contains 45.67 mg glucose in 1 ml (i.e. 13.702 g in 300 ml solution). This should be taken into account in patients with diabetes.
Sodium
This medicinal product contains 113 mg sodium in 300 ml solution, equivalent to 5.65% of the WHO recommended maximum daily intake of 2 g sodium for adults. This should be taken into account in patients who require sodium intake control in their diet.
The sodium content originating from the diluent should be considered when calculating the total sodium content in the prepared diluted solution. For accurate information on the sodium content in the solution used for dilution, refer to the Summary of Product Characteristics.

Interactions
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). There are only limited data from drug interaction studies and on the safety of linezolid use in patients concurrently receiving drugs that may inhibit monoamine oxidase (MAO). Therefore, linezolid should not be used unless close monitoring and patient control are possible.

Interactions that may increase blood pressure
In healthy volunteers with normal blood pressure, linezolid has been shown to potentiate the increase in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant use of linezolid and pseudoephedrine or phenylpropanolamine resulted in an increase in systolic blood pressure of 30–40 mmHg, compared to an increase 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 patients with hypertension. Gradual dose adjustment of vasoactive drugs, including those acting on dopaminergic receptors, is recommended when used concomitantly with linezolid.

Serotonergic interactions
Interactions between linezolid and dextromethorphan were studied in healthy volunteers. Dextromethorphan (two 20 mg doses administered 4 hours apart) was given to patients with or without concomitant linezolid. No symptoms of serotonin syndrome (disorientation, delirium, restlessness, tremor, facial flushing, increased sweating, very high fever) were observed in patients receiving both linezolid and dextromethorphan.
After marketing authorization: one case of symptoms resembling serotonin syndrome was reported after concomitant administration of linezolid and dextromethorphan; symptoms resolved after discontinuation of both drugs.
During clinical trials, cases of serotonin syndrome were reported during concomitant use of linezolid and serotonergic drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, concomitant administration is not recommended.

Use with tyramine-rich foods
No clinically significant increase in blood pressure was observed in patients receiving linezolid together with less than 100 mg tyramine. This indicates that only excessive consumption of foods and beverages high in tyramine (e.g. aged cheeses, yeast extracts, non-distilled alcoholic beverages and fermented soy products such as soy sauce) should be avoided.

Medicinal products metabolized by cytochrome P450
Linezolid is not significantly metabolized by the cytochrome P450 (CYP450) enzyme system and does not inhibit the activity of any human CYP isoenzymes of clinical significance (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, CYP450-mediated interactions with other medicinal products are not expected during linezolid treatment.

Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy men who received 600 mg linezolid twice daily for 2.5 days or linezolid with 600 mg rifampicin once daily for 8 days. Rifampicin reduced Cmax and AUC of linezolid by 21% [90% CI, 15, 27] and 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin
If warfarin is added during linezolid treatment after steady-state concentrations are achieved, a 10% decrease in mean maximum INR (International Normalized Ratio) values and a 5% decrease in the area under the INR curve (AUC) occur. There are insufficient data to determine the clinical significance of concomitant use of linezolid and warfarin.

Effects on fertility, pregnancy and lactation
Pregnancy
There are insufficient data on the use of linezolid in pregnant women. Animal studies have shown toxic effects of linezolid on reproduction. There is a risk when using the drug in humans.
Linezolid should not be used during pregnancy unless absolutely necessary, i.e. only when the expected benefit outweighs the theoretical risk.

Breastfeeding
Animal studies indicate that linezolid and its metabolites may pass into breast milk; therefore, breastfeeding must be discontinued before starting linezolid treatment and not resumed during treatment.

Fertility
Animal studies have shown that linezolid causes reduced fertility. It is not known whether linezolid affects fertility in humans.

Effects on ability to drive and use machines
Patients should be warned that dizziness and visual disturbances may occur during treatment with linezolid and that they should not drive or operate machinery during such episodes.

Overdose
No specific antidote is known.
No cases of linezolid overdose have been reported. Nevertheless, the following information may be useful in managing overdose.
Supportive treatment to maintain vital functions and maintenance of glomerular filtration are recommended. Approximately 30% of a dose of linezolid is removed from the body during a 3-hour hemodialysis session; however, there are no data on the removal of linezolid by peritoneal dialysis or hemoperfusion.

Instructions for use
The packaging is intended for single use only. Before administration, check for leakage by firmly squeezing the polyethylene bag for one minute. If the bag leaks, do not use the product, as it may not be sterile. Before administration, inspect the solution; it should be administered only if clear and free from particulate matter. After checking the integrity of the bag and removing the protective film, connect the polyethylene bag to an administration set with a double-lumen needle.
Do not use polyethylene bags in series connections. Discard any unused solution. Do not connect bags with partially used contents.

Compatibility
Linezolid Polpharma, infusion solution, is compatible with the following solutions: 5% glucose infusion solution, 0.9% sodium chloride infusion solution, Ringer's lactate injection solution.

Incompatibilities
Do not add other substances to the solution. If linezolid is to be administered concomitantly with other drugs, each drug should be administered separately, according to its administration recommendations. If linezolid and other drugs are to be administered alternately through the same intravenous access, they should be flushed with a compatible solution before and after administration of linezolid.
Linezolid Polpharma infusion solution is physically incompatible with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin and sulfamethoxazole with trimethoprim. Additionally, it is chemically incompatible with sodium ceftriaxone.

Shelf life
Before opening: 30 months.
After opening: chemical and physical stability has been demonstrated for 2 hours at 25°C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the user is solely responsible for the duration and conditions of storage during use.

Special precautions for storage
No special temperature storage requirements.
Store the polyethylene bag in its outer packaging to protect from light.
Any unused portion of this product or waste material should be disposed of in accordance with local regulations.