Linezolid Krka

Package Leaflet: Information for the User

Linezolid Krka, 2 mg/ml, Solution for Infusion

Linezolidum

Read the Package Leaflet Carefully Before Using the Medicinal Product, as it Contains Important Information for the Patient.

• The package leaflet should be kept for future reference, in case it needs to be re-read.
• In case of any doubts, the patient should consult a doctor, pharmacist, or nurse.
• If the patient experiences any side effects, including those not listed in the package leaflet, they should inform their doctor, pharmacist, or nurse. See section 4.

Table of Contents of the Package Leaflet

• 1. What is Linezolid Krka and What is it Used For
• 2. Important Information Before Using Linezolid Krka
• 3. How to Use Linezolid Krka
• 4. Possible Side Effects
• 5. How to Store Linezolid Krka
• 6. Contents of the Package and Other Information

1. What is Linezolid Krka and What is it Used For

Linezolid Krka is an antibiotic belonging to the class of oxazolidinone antibiotics, which works by stopping the growth of certain bacteria that cause infections in adults. This medicinal product is used to treat pneumonia, certain skin and soft tissue infections. The doctor will decide whether the use of Linezolid Krka is appropriate for the treatment of a specific infection.

2. Important Information Before Using Linezolid Krka

When Not to Use Linezolid Krka

• if the patient is allergic to linezolid or any of the other ingredients of this medicinal product (listed in section 6);
• if the patient is currently taking or has taken within the last 2 weeks monoamine oxidase inhibitors (MAOIs, e.g., phenelzine, isocarboxazid, selegiline, moclobemide). These medicinal products may be used to treat depression or Parkinson's disease;
• during breastfeeding, as linezolid passes into breast milk and may harm the baby.

Warnings and Precautions

Before starting treatment with Linezolid Krka, the patient should discuss it with their doctor, pharmacist, or nurse. Linezolid Krka may not be suitable for the patient if they can answer "yes" to any of the following questions. In such a case, the patient should talk to their doctor, as it may be necessary to check their overall health and blood pressure before and during treatment. The doctor may also decide to use a different medicinal product. If the patient is unsure whether the following situations apply to them, they should consult their doctor.

• Does the patient have high blood pressure and are they taking medicinal products for it, or not?
• Has the patient been diagnosed with hyperthyroidism?
• Does the patient have a pheochromocytoma (a tumor of the adrenal gland) or a carcinoid syndrome (a condition caused by tumors in the hormonal system, which can cause symptoms such as diarrhea, flushing, and wheezing)?
• Does the patient have bipolar disorder, schizoaffective disorder, disorientation, or other psychiatric disorders?
• Has the patient experienced hyponatremia (low sodium levels in the blood) or are they taking medicinal products that lower sodium levels in the blood, such as certain diuretics (also known as "water pills"), e.g., hydrochlorothiazide?
• Is the patient taking any opioid medicinal products? The concomitant use of certain medicinal products, including antidepressants and opioids, with Linezolid Krka may lead to the development of serotonin syndrome, a potentially life-threatening condition (see section 2 "Linezolid Krka and Other Medicinal Products" and section 4).

When to Exercise Caution When Using Linezolid Krka

The patient should inform their doctor before taking Linezolid Krka if they have:

• advanced age,
• a tendency to bruise or bleed,
• anemia (low red blood cell count),
• a tendency to infections,
• a history of seizures,
• liver or kidney dysfunction, especially if the patient is on dialysis,
• diarrhea.

The patient should immediately inform their doctor if they experience:

• vision problems, such as blurred vision, changes in color vision, difficulty seeing details, or narrowing of the visual field;
• loss of sensation in their hands or feet or a feeling of tingling or numbness in their hands and feet;
• diarrhea during or after treatment with antibiotics, including Linezolid Krka; in case of severe or persistent diarrhea, blood or mucus in the stool, the patient should immediately stop taking Linezolid Krka and consult their doctor; in such cases, the patient should not take medicinal products that slow down bowel movements;
• recurring nausea or vomiting, abdominal pain, or rapid breathing;
• unexplained muscle pain, tenderness, or weakness and (or) dark urine color. These may be symptoms of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage;
• nausea and malaise, including muscle weakness, headache, confusion, and memory disorders, which may indicate hyponatremia (low sodium levels in the blood).

Linezolid Krka and Other Medicinal Products

There is a risk of interactions between Linezolid Krka and other medicinal products. These interactions may lead to the development of side effects, such as changes in blood pressure, body temperature, or heart rate. The patient should tell their doctor about all the medicinal products they are currently taking or have recently taken, as well as any medicinal products they plan to take.

The Patient Should Inform Their Doctor About the Use of the Following Medicinal Products

because Linezolid Krka should not be used during treatment with or shortly after treatment with these medicinal products (see also section 2 above: "When Not to Use Linezolid Krka"):

• monoamine oxidase inhibitors (MAOIs: e.g., phenelzine, isocarboxazid, selegiline, moclobemide); these medicinal products may be used to treat depression or Parkinson's disease.

The patient should also inform their doctor if they are taking any of the following medicinal products. The doctor may still prescribe Linezolid Krka, but it will be necessary to monitor the patient's overall health and blood pressure before and during treatment. In other cases, the doctor may decide that a different medicinal product would be more suitable for the patient.

• Medicinal products used to treat congestion, such as pseudoephedrine or phenylpropanolamine, which are used to treat colds or flu.
• Certain asthma medicinal products, such as salbutamol, terbutaline, or fenoterol.
• Tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). Many medicinal products belong to these classes, such as amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, or sertraline.
• Migraine medicinal products, such as sumatriptan or zolmitriptan.
• Medicinal products used to treat severe allergic reactions, such as adrenaline (epinephrine).
• Medicinal products that increase blood pressure, such as noradrenaline (norepinephrine), dopamine, or dobutamine.
• Opioids, such as pethidine, which are used to treat moderate to severe pain.
• Medicinal products used to treat anxiety disorders, such as buspirone.
• Anticoagulant medicinal products, such as warfarin.
• The antibiotic rifampicin.

Linezolid Krka with Food and Drink

• Linezolid Krka can be taken with or without food.
• During treatment, the patient should limit their consumption of foods that contain tyramine, such as mature cheese, yeast extracts, and soy products, as well as alcoholic beverages, especially beer and wine. These products can interact with Linezolid Krka, leading to increased blood pressure.
• If the patient experiences a throbbing headache after eating or drinking, they should immediately consult their doctor, pharmacist, or nurse.

Pregnancy, Breastfeeding, and Fertility

The effects of linezolid in pregnant women are unknown. Therefore, unless the doctor advises otherwise, Linezolid Krka should not be used during pregnancy. If the patient is pregnant, breastfeeding, or thinks they may be pregnant, or are planning to have a baby, they should consult their doctor or pharmacist before using this medicinal product. During treatment with Linezolid Krka, the patient should not breastfeed, as this medicinal product passes into breast milk and may harm the baby.

Driving and Using Machines

Linezolid Krka may cause dizziness or vision disturbances. In such cases, the patient should not drive or operate machines. The patient should remember that feeling unwell can affect their ability to drive or operate machines.

Linezolid Krka Contains Glucose

300 ml of the solution for infusion contains 13.7 g of glucose. This should be taken into account in patients with diabetes.

Linezolid Krka Contains Sodium

300 ml of the solution for infusion contains 114 mg of sodium (the main component of common salt). This corresponds to 5.7% of the maximum recommended daily intake of sodium in the diet for adults.

3. How to Use Linezolid Krka

Adults

This medicinal product should always be used exactly as described in this package leaflet or as directed by the doctor, pharmacist, or nurse. In case of doubts, the patient should consult their doctor, pharmacist, or nurse. The medicinal product will be administered by a doctor or healthcare professional as an intravenous infusion. The usual dose for adults (18 years and older) is 300 ml of the solution (600 mg of linezolid) twice a day, administered directly into the bloodstream (intravenously) as an infusion, over 30 to 120 minutes. In patients undergoing dialysis, Linezolid Krka should be administered after dialysis. Treatment usually lasts from 10 to 14 days, but it may last up to 28 days. The efficacy and safety of using this medicinal product for periods longer than 28 days have not been established. The doctor will decide on the necessary duration of treatment. During treatment with Linezolid Krka, the doctor will recommend regular blood tests to monitor the patient's blood count.

Use in Children and Adolescents

Linezolid Krka is not usually used to treat children and adolescents (under 18 years of age).

Overdose

In case the patient thinks they have received too much of the medicinal product, they should immediately consult their doctor or nurse.

Missed Dose

Since the medicinal product will be administered under close medical supervision, missing a dose is unlikely. However, if the patient suspects they have missed a dose, they should immediately inform their doctor or nurse. The patient should not take a double dose to make up for a missed dose. In case of any further doubts about using this medicinal product, the patient should consult their doctor, pharmacist, or nurse.

4. Possible Side Effects

Like all medicinal products, Linezolid Krka can cause side effects, although not everybody gets them. If the patient experiences any of the following side effects during treatment with Linezolid Krka, they should immediately inform their doctor, nurse, or pharmacist:

• severe skin reactions (not very common), swelling, especially in the face and neck (not very common), wheezing, and (or) difficulty breathing (rare). These may be symptoms of an allergic reaction, and it may be necessary to stop using Linezolid Krka. Skin reactions, such as: a purple, raised rash caused by inflammation of blood vessels (rare); redness, peeling of the skin (skin inflammation) (not very common), rash (common), itching (common).
• vision disturbances (not very common), such as blurred vision (not very common), changes in color vision (frequency not known), difficulty seeing details (frequency not known), or narrowing of the visual field (rare).
• severe diarrhea with blood and (or) mucus in the stool (antibiotic-associated colitis, including pseudomembranous colitis), which can rarely lead to life-threatening complications (not very common).
• recurring nausea or vomiting, abdominal pain, or rapid breathing (rare).
• seizures have been reported during treatment with Linezolid Krka (not very common).
• serotonin syndrome (frequency not known): the patient should inform their doctor if they experience symptoms such as excessive stimulation, confusion, hallucinations, stiffness, tremors, lack of coordination, seizures, rapid heartbeat, serious breathing problems, and diarrhea (suggesting serotonin syndrome) (see section 2).
• bleeding or bruising of unknown cause, which may be due to changes in blood cell count, affecting blood clotting or leading to anemia (common).
• changes in the number of certain blood cells, which may affect the patient's ability to fight infections (not very common), symptoms of infection include: fever (common), sore throat (not very common), mouth ulcers (not very common), fatigue (not very common).
• rhabdomyolysis (rare): objective and subjective symptoms include unexplained muscle pain, tenderness, or weakness and (or) dark urine color. These may be symptoms of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• pancreatitis (not very common).
• seizures (not very common).
• transient ischemic attacks (transient cerebral ischemia, causing short-term symptoms such as loss of vision, weakness of limbs, slurred speech, loss of consciousness) (not very common).
• "ringing" in the ears (tinnitus) (not very common).

In patients who received Linezolid Krka for more than 28 days, numbness, tingling, or blurred vision have been reported. If the patient experiences vision disturbances, they should immediately consult their doctor.

Additional Side Effects Include:

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

• fungal infections, especially vaginal or oral thrush
• headache
• metallic taste in the mouth
• diarrhea, nausea, or vomiting
• changes in some blood test results, including those measuring proteins, salts, or enzymes, used to assess kidney or liver function, or blood sugar levels
• sleep disturbances
• increased blood pressure
• anemia (low red blood cell count)
• dizziness
• local or generalized abdominal pain
• constipation
• digestive disorders (dyspepsia)
• local pain
• decreased platelet count

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

• vaginal or genital fungal infections in women
• feeling of numbness or tingling
• swelling, pain, or discoloration of the tongue
• dry mouth
• pain or inflammation at the infusion site
• phlebitis (inflammation of the vein, including at the infusion site)
• frequent urination
• chills
• increased thirst
• increased sweating
• hyponatremia (low sodium levels in the blood)
• kidney dysfunction
• bloating
• pain at the injection site
• increased creatinine levels
• abdominal pain
• changes in heart rate (e.g., increased heart rate)
• decreased count of all types of blood cells
• weakness and (or) changes in sensation

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

• superficial tooth discoloration, which can be removed by dental cleaning (manual scaling)

Other Side Effects Have Also Been Reported(frequency not known: frequency cannot be estimated from the available data):

• hair loss (alopecia)

Reporting Side Effects

If the patient experiences any side effects, including those not listed in the package leaflet, they should inform their doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety, 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 authorization holder. By reporting side effects, more information can be gathered on the safety of this medicinal product.

5. How to Store Linezolid Krka

The medicinal product should be stored out of sight and reach of children. Do not use this medicinal product after the expiry date stated on the packaging after "EXP". The expiry date refers to the last day of the month stated. Do not store above 30°C. Store in the original packaging to protect from light. After opening:the chemical and physical stability of the solution in the infusion bag has been demonstrated for 24 hours at room temperature, after removal from the outer bag. For microbiological reasons, the medicinal product should be used immediately. If not used immediately, the responsibility for the storage conditions and the storage period lies with the user. Do not use the medicinal product if the solution is not clear, colorless to yellow or yellow-brown. Medicinal products should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicinal products they no longer need. This will help protect the environment.

6. Contents of the Package and Other Information

What Linezolid Krka Contains

• The active substance is linezolid. 1 ml of the solution for infusion contains 2 mg of linezolid. A 300 ml infusion bag contains 600 mg of linezolid.
• The other ingredients are glucose monohydrate, sodium citrate dihydrate, citric acid, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), and water for injections. See section 2 "Linezolid Krka Contains Glucose" and "Linezolid Krka Contains Sodium".

What Linezolid Krka Looks Like and Contents of the Package

Clear solution, colorless to yellow or yellow-brown (pH: 4.6-5.2; osmolality: 270 mOsmol/kg - 320 mOsmol/kg). Primary packaging: 300 ml infusion bag made of multi-layered polyolefin film, with a multi-layered polyolefin port and a polyolefin twist-off connector. Outer packaging: multi-layered outer bag made of polyester/aluminum/polyester/polypropylene, in a cardboard box. The outer bags are packaged in cardboard boxes containing 1 or 10 infusion bags. Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

This Medicinal Product is Authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) Under the Following Names:

For more information about this medicinal product, the patient should contact their local representative of the marketing authorization holder: KRKA-POLSKA Sp. z o.o., ul. Równoległa 5, 02-235 Warsaw, Tel. 22 57 37 500

Date of Last Revision of the Package Leaflet: 30.05.2025

Special Warnings and Precautions for Use

Myelosuppression
In patients treated with linezolid, myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been observed. In cases where this effect of linezolid was diagnosed, after the end of treatment with the drug, the changed blood test results returned to pre-treatment values. The occurrence of such symptoms appears to be related to the duration of treatment. In elderly patients treated with linezolid, there is a greater risk of blood count disorders than in younger patients. Thrombocytopenia may occur more frequently in patients with severe renal insufficiency, regardless of whether they are undergoing dialysis. Therefore, blood cell count should be strictly controlled: in patients with pre-existing anemia, granulocytopenia, or thrombocytopenia, in patients taking medications that may decrease hemoglobin levels, blood cell count, or affect platelet count or function, in patients with severe renal insufficiency, and in patients taking linezolid for more than 10 to 14 days. Linezolid can be administered to these patients only if strict control of hemoglobin levels, blood cell count, and platelet count is possible. If significant myelosuppression occurs during linezolid treatment, the medicinal product should be discontinued, unless administration of the medicinal product is absolutely necessary. In this case, careful control of blood morphology parameters and implementation of appropriate measures should be carried out.
In addition, in patients receiving linezolid, it is recommended to determine the complete peripheral blood count (with hemoglobin level, platelet count, and white blood cell count with smear) weekly, regardless of the initial blood morphology picture.
In studies involving the administration of linezolid in exceptional cases before its approval (compassionate use), an increased frequency of severe anemia was noted in patients who received linezolid for more than the maximum recommended 28 days. In these patients, blood transfusions were more frequently required. Cases of anemia requiring blood transfusion were also reported after the introduction of linezolid to the market, more often after use for more than 28 days.
After the introduction of linezolid to the market, cases of sideroblastic anemia have been reported. Most patients who first experienced symptoms received linezolid for more than 28 days. After the end of linezolid treatment, anemia, both treated and untreated, completely or partially resolved in most patients.
Variable Mortality in Clinical Trials in Patients with Gram-Positive Bacterial Infections Related to Central Venous Catheter Use
In an open clinical trial in critically ill patients with central venous catheter-related infections, higher mortality was observed in patients receiving linezolid than in patients treated with vancomycin, dicloxacillin, or oxacillin [78/363 (21.5%) versus 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 infections 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 with any other pathogen or without a pathogen at the start of treatment (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 were colonized by pathogenic Gram-negative microorganisms and died due to Gram-negative bacterial infections and mixed infections. In connection with the above, in complicated skin and soft tissue infections, linezolid can be used in patients with suspected or confirmed concurrent Gram-negative bacterial infection only when other treatment options are not available. In such cases, it is necessary to start simultaneous treatment against Gram-negative bacteria.
Antibiotic-Associated Diarrhea and Colitis
During the use of almost any antibacterial drug, including linezolid, the occurrence of pseudomembranous colitis and antibiotic-associated diarrhea, including Clostridium difficileinfection, has been reported. This complication can range from mild diarrhea to life-threatening colitis. Therefore, it is essential to consider this diagnosis in patients who develop severe diarrhea after using linezolid. If suspected or confirmed that diarrhea or colitis is related to antibiotic use, it is recommended to discontinue the antibacterial drug, including linezolid, and start appropriate treatment immediately. In this situation, the use of drugs that inhibit intestinal peristalsis is contraindicated.
Lactic Acidosis
During the use of linezolid, cases of lactic acidosis have been reported. In patients who develop objective and subjective symptoms of metabolic acidosis, including recurring nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, while taking linezolid, immediate medical intervention is necessary. If lactic acidosis occurs, the risk-benefit ratio of continuing linezolid treatment should be evaluated before continuing.
Mitochondrial Disorders
Linezolid inhibits mitochondrial protein synthesis, which can lead to adverse effects such as lactic acidosis, anemia, and neuropathy (optic or peripheral). These symptoms occur more frequently when linezolid is used for more than 28 days.
Serotonin Syndrome
Spontaneous reports have described cases of serotonin syndrome associated with the concomitant use of linezolid and serotonergic drugs, including antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and opioids (see SPC, section 4.5). Therefore, concomitant use of linezolid with serotonergic medicinal products is contraindicated (see SPC, section 4.3), unless it is necessary.
It is necessary to carefully observe whether the patient does not experience subjective and objective symptoms of serotonin syndrome, such as cognitive impairment, very high fever, hyperreflexia, and lack of coordination. If symptoms occur, the doctor should consider discontinuing treatment with one or both drugs. After discontinuing serotonergic drugs, withdrawal symptoms may occur.
Rhabdomyolysis
Cases of rhabdomyolysis associated with the use of linezolid have been reported. Linezolid should be used with caution in patients with factors predisposing to rhabdomyolysis. If symptoms of rhabdomyolysis occur, linezolid should be discontinued and appropriate treatment initiated.
Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
In some patients treated with linezolid, cases of hyponatremia and/or SIADH have been observed. In patients at risk of hyponatremia, such as elderly patients or those taking drugs that may decrease sodium levels in the blood (e.g., thiazide diuretics, such as hydrochlorothiazide), regular monitoring of sodium levels in serum is recommended.
Peripheral Neuropathy and Optic Neuropathy
In patients treated with linezolid, cases of peripheral neuropathy and optic neuropathy have been reported, sometimes leading to vision loss; these reports mainly concerned patients treated for more than the maximum recommended 28 days.
Each patient should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defects. In such cases, it is recommended to refer the patient for an ophthalmological examination immediately. If the patient is taking linezolid for more than the recommended maximum of 28 days, regular monitoring of visual function is necessary.
If peripheral neuropathy or optic neuropathy occurs, the possibility of continuing linezolid treatment should be evaluated based on the risk-benefit ratio.
The risk of neuropathy may be increased during the administration of linezolid to patients currently or recently taking antitubercular drugs.
Seizures
In patients treated with linezolid, seizures have been reported. In most of these cases, a history of seizures or risk factors was noted.
Patients should be advised to tell their doctor if they have had seizures in the past.
Monoamine Oxidase Inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). However, at the doses used to treat infections, it does not have an antidepressant effect. Only limited data are available on the interactions of linezolid with other drugs and the safety of its use in patients with other diseases and/or taking other drugs that may pose a risk associated with MAO inhibition. Linezolid should not be used in such cases, unless close observation and monitoring of the patient are possible.
Consumption of Tyramine-Rich Foods
The patient should be instructed to limit the consumption of tyramine-rich foods during linezolid treatment.
Superinfections
In clinical trials, the impact of linezolid on the physiological bacterial flora was not evaluated.
The use of antibiotics can sometimes cause excessive growth of non-susceptible microorganisms.
For example, during a clinical trial, approximately 3% of patients receiving the recommended doses of linezolid developed drug-induced candidiasis. If superinfection with non-susceptible microorganisms occurs during linezolid treatment, appropriate treatment should be initiated.
Special Patient Groups
In patients with severe renal insufficiency, linezolid should be used with caution and only when the expected benefit outweighs the theoretical risk (see SPC, sections 4.2 and 5.2).
In patients with severe hepatic insufficiency, linezolid should be used only when the expected benefit outweighs the risk.
Fertility Disorders
The use of linezolid led to a transient decrease in fertility and induced abnormalities in sperm morphology in adult male rats exposed to linezolid at levels similar to those in humans. There are no data on the effect of linezolid on the male reproductive system in humans.
Clinical Trials
The safety and efficacy of administering linezolid for more than 28 days have not been established.
No controlled clinical trials have been conducted in patients with diabetic foot, decubitus ulcers, ischemic changes, severe burns, or gangrene. Experience with the use of linezolid in such cases is limited.
Excipients
300 ml of solution contains 13.7 g of glucose. This should be taken into account in patients with diabetes.
300 ml of solution also contains 114 mg (5 mmol) of sodium, which corresponds to 5.7% of the WHO-recommended maximum daily intake of 2 g of sodium for adults.

Interactions

Monoamine Oxidase Inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are only limited data available from studies on the interactions of linezolid with other drugs and the safety of its use in patients taking other drugs that may inhibit monoamine oxidase (MAO). Linezolid should not be used in such cases, unless close observation and monitoring of the patient are possible.
Potential Interactions Leading to Increased Blood Pressure
It has been shown that in healthy volunteers, linezolid enhances the increase in arterial blood pressure caused by pseudoephedrine and phenylpropanolamine. 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 when linezolid was used alone, 14-18 mmHg when pseudoephedrine or phenylpropanolamine was used alone, and 8-11 mmHg when placebo was used. Similar studies have not been conducted in patients with hypertension. It is recommended to gradually adjust the dose of vasoconstrictive drugs (including drugs acting on dopaminergic receptors) during their concomitant use with linezolid.
Potential Interactions with Serotonin Receptor Agonists
In healthy volunteers, interactions between linezolid and dextromethorphan have been studied.
Dextromethorphan (2 doses of 20 mg administered with a 4-hour interval) was administered concomitantly with linezolid or without it. In patients receiving linezolid and dextromethorphan, no symptoms of serotonin syndrome (such as disorientation, hallucinations, agitation, tremors, flushing, sweating, and very high fever) were observed.
After the introduction of linezolid to the market, one case of symptoms similar to serotonin syndrome after concomitant administration of linezolid and dextromethorphan has been reported. The symptoms resolved after discontinuation of both drugs.
During clinical trials, cases of serotonin syndrome have been reported during concomitant use of linezolid and serotonergic drugs, including antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and opioids. Therefore, their concomitant use is not recommended (see SPC, section 4.3). The management of patients who require concomitant use of linezolid and serotonergic drugs is described in the special warnings and precautions for use.
Use with Tyramine-Rich Foods
No significant increase in blood pressure was observed in patients receiving linezolid and a tyramine dose of less than 100 mg. This suggests that it is only necessary to avoid consuming excessive amounts of tyramine-rich foods and drinks (e.g., mature cheeses, yeast extracts, undistilled alcoholic beverages, and products derived from fermented soybean seeds, such as soy sauce).
Drugs Metabolized by Cytochrome P450
Linezolid is not significantly metabolized by the cytochrome P450 enzyme system (CYP450) 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 CYP isoenzymes in rats. Therefore, it can be expected that during the use of linezolid, no interactions with CYP450 will occur.
Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid has been studied in 16 healthy men who received 600 mg of linezolid twice daily for 2.5 days or linezolid with 600 mg of rifampicin once daily for 8 days. Rifampicin decreased the C and AUC of linezolid by an average 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
If warfarin is added to treatment with linezolid after reaching steady-state levels, a 10% decrease in mean maximum INR (International Normalized Ratio) values and a 5% decrease in the area under the INR curve are observed. 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 limited data on the use of linezolid in pregnant women. Animal studies have shown a toxic effect of linezolid on fertility. There is a potential risk in humans.
Linezolid should not be used during pregnancy, unless the doctor considers that the benefits outweigh the potential risk.
Breastfeeding
Studies in animals suggest that linezolid and its metabolites may pass into breast milk, and therefore, breastfeeding should be discontinued before and during treatment with linezolid.
Fertility
In animal studies, linezolid caused a decrease in fertility.

Effects on Ability to Drive and Use Machines

The patient should be warned that during linezolid treatment, dizziness and symptoms related to vision disorders may occur, and they should not drive vehicles or operate machines.

Adverse Reactions

Adverse events listed in the table below occurred with a frequency specified in clinical trials conducted in over 6,000 adult patients who received linezolid in recommended doses for a period not exceeding 28 days.
The most commonly reported adverse events were: diarrhea (8.9%), nausea (6.9%), and vomiting (4.3%), as well as headache (4.2%).
The most commonly reported adverse events related to linezolid use that led to discontinuation of treatment were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to an adverse event related to linezolid use.
Additional adverse reactions reported after the drug was marketed are listed in the table below and are described as "frequency unknown" because their actual frequency cannot be determined based on available data.
The following adverse reactions of linezolid were observed with the following frequency:

• very common (≥ 1/10),
• common (≥ 1/100 to <1>
• uncommon (≥ 1/1000 to <1>
• rare (≥ 1/10 000 to <1>
• very rare (<1>
• frequency unknown (frequency cannot be determined based on available data).

The following adverse reactions of linezolid rarely had a severe course: localized abdominal pain, transient ischemic attacks, and hypertension.
†In controlled clinical trials, in which linezolid was administered for up to 28 days, anemia occurred in 2% of patients. In studies involving the administration of linezolid in exceptional cases before its approval (compassionate use) in patients with life-threatening infections and concomitant diseases, anemia developed in 2.5% (33/1326) of patients treated with linezolid for up to 28 days and in 12.3% (53/430) of patients treated for more than 28 days. Severe anemia associated with linezolid use, requiring blood transfusion, occurred in 9% (3/33) of patients treated for up to 28 days and in 15% (8/53) of patients treated for more than 28 days.
Children and Adolescents
Data on safety obtained in clinical trials, in which over 500 patients from birth to 17 years of age participated, do not indicate that the safety profile of linezolid in the pediatric population differs from that observed in adult patients.

Overdose

There is no specific antidote.
No cases of linezolid overdose have been reported. Nevertheless, the following information may be useful in the event of an overdose:
Supportive care and maintenance of renal function should be provided. Approximately 30% of the linezolid dose 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.

Special Precautions for Disposal and Preparation of the Medicinal Product for Administration

For single use only. The outer bag should be removed immediately before administration, and the bag should be checked for minor leaks by squeezing it firmly. If the bag is leaking, the product should not be used, as it may not be sterile. Before administration, the solution should be inspected. It can only be administered if it is clear and does not contain particulate matter. Bags should not be connected in series. Unused solution residues should be discarded. There are no special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local regulations. Partially used bags should not be connected.

Incompatibilities

Linezolid Krka solution for infusion is compatible with the following solutions: 5% glucose solution for infusion, 0.9% sodium chloride solution for infusion, Ringer's solution with lactate for injection (Hartmann's solution for injection).

Shelf Life

2 years
After opening:the chemical and physical stability of the solution in the infusion bag has been demonstrated for 24 hours at room temperature, after removal from the outer packaging (outer bag). For microbiological reasons, the product should be used immediately. If the product is not used immediately, the responsibility for the storage conditions and duration lies with the user.

Special Precautions for Storage

Do not store above 30°C.
Store in the original packaging to protect from light.