Levotren

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOTREN (LEVOTREN)

Composition:

Active substance: levofloxacin;

1 ml of solution contains levofloxacin (as hemihydrate) 5 mg;

Excipients: sodium chloride, hydrochloric acid concentrated, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear solution.

Pharmacotherapeutic group. Antibacterials for systemic use. Antibacterials of the quinolone group. Fluoroquinolones. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S(‑) enantiomer of the racemic active substance ofloxacin.

Mechanism of action. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA gyrase and topoisomerase IV complex.

Pharmacokinetic/pharmacodynamic relationship. The degree of antibacterial activity of levofloxacin depends on the ratio of peak serum concentration (Cmax) or area under the concentration-time curve (AUC) to minimum inhibitory (suppressive) concentration [MIC (MBC)].

Mechanism of resistance. Resistance to levofloxacin develops through a stepwise process of mutations in genes encoding both type II topoisomerases: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as reduced permeability (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance exists between levofloxacin and other fluoroquinolones.

Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.

Breakpoints. The recommended EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints for levofloxacin MIC values, which differentiate susceptible microorganisms from moderately susceptible (intermediately resistant) organisms, and moderately susceptible from resistant organisms, are presented in the table 1 below for MIC testing (mg/l).

EUCAST clinical breakpoints for levofloxacin (version 10.0, 2020-01-01):

Table 1

Pathogen	Susceptible	Resistant
Enterobacterales	≤ 0.5 mg/l	> 1 mg/l
Pseudomonas spp.	≤ 0.001 mg/l	> 1 mg/l
Acinetobacter spp.	≤ 0.5 mg/l	> 1 mg/l
Staphylococcus aureus Coagulase-negative staphylococci	≤ 0.001 mg/l	> 1 mg/l
Enterococcus spp.1	≤ 4 mg/l	> 4 mg/l
Streptococcus pneumoniae	≤ 0.001 mg/l	> 2 mg/l
Streptococcus A,B,C and G	≤ 0.001 mg/l	> 2 mg/l
Haemophilus influenzae	≤ 0.06 mg/l	> 0.06 mg/l
Moraxella catarrhalis	≤ 0.125 mg/l	> 0.125 mg/l
Helicobacter pylori	≤ 1 mg/l	> 1 mg/l
Aerococcus sanguinicola and urinae2	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
PK-PD (non-species-related) breakpoint values	≤ 0.5 mg/l	> 1 mg/l
1 Uncomplicated urinary tract infections only. 2 Susceptibility depends on ciprofloxacin susceptibility.

The prevalence of resistance may vary geographically and over time for selected species. Local information on resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the medicinal product doubtful, at least for certain types of infections.

Generally susceptible species

Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci – groups C and G*, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria: Peptostreptococcus.

Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species that may develop resistance

Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Coagulase-negative Staphylococcus spp.

Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria: Bacteroides fragilis.

Naturally resistant strains

Aerobic gram-positive bacteria: Enterococcus faecium.

* Methicillin-resistant S. aureus is likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with Cmax reached within 1–2 hours. Absolute bioavailability is approximately 99–100%.

Food has a negligible effect on the absorption of levofloxacin.

Steady-state conditions are achieved after one or two doses of 500 mg according to the dosing regimen within 48 hours.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma.

The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into tissues and body fluids

Levofloxacin penetrates well into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (bulla fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal (CSF) fluid.

Biotransformation

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the drug excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). It is primarily excreted by the kidneys (over 85% of the administered dose). The mean total systemic clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin between intravenous and oral administration, indicating that oral and intravenous routes are interchangeable.

Linearity

Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 1000 mg.

Special patient groups

Patients with renal impairment

Renal function impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-life increases, as shown in Table 2 below.

Table 2

Pharmacokinetics in renal impairment after a single oral 500 mg dose

Creatinine clearance (mL/min)	< 20	20–49	50–80
Renal clearance (mL/min)	13	26	57
Elimination half-life (hours)	35	27	9

Geriatric patients

There are no significant differences in the pharmacokinetics of levofloxacin in younger patients and elderly patients, except for differences related to creatinine clearance.

Gender differences

Separate analysis of male and female patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

The medicinal product Levotren is indicated for the treatment of the following infections in adults:

• Acute pyelonephritis and complicated urinary tract infections (see section "Special precautions for use");
• Chronic bacterial prostatitis;
• Pulmonary form of anthrax: post-exposure prophylaxis and treatment (see section "Special precautions for use").

For the treatment of the following infections, the medicinal product Levotren should be used only when it is considered inappropriate to use antibacterial agents usually recommended for the treatment of such infections:

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections.

Official recommendations on appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to levofloxacin, to other quinolones, or to any of the excipients of the medicinal product;
• Epilepsy;
• Tendon disorders associated with prior fluoroquinolone therapy;
• Pediatric age (under 18 years);
• Pregnancy;
• Breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on Levotren

Theophylline, fenbufen, or similar non-steroidal anti-inflammatory medicinal products

No pharmacokinetic interaction between levofloxacin and theophylline was observed in clinical trials. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce the seizure threshold.

Levofloxacin concentration is approximately 13% higher in the presence of fenbufen than when levofloxacin is administered alone.

Probenecid and cimetidine

Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin.

Renal clearance was reduced in the presence of cimetidine (by 24%) and probenecid (by 34%). This is explained by the fact that both drugs are capable of blocking the tubular secretion of levofloxacin. However, when using the doses tested in the study, statistically significant kinetic differences are unlikely to have clinical significance.

Concomitant use of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Other medicinal products

Clinical pharmacology studies did not demonstrate a clinically significant effect on the pharmacokinetics of levofloxacin when levofloxacin was administered concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of the medicinal product Levotren on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products that may prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotic medicinal products) (see section "Special precautions for use" ("QT interval prolongation")).

Theophylline

In pharmacodynamic interaction studies, levofloxacin did not affect the pharmacokinetics of theophylline (a marker substrate for CYP1A2), indicating that levofloxacin does not inhibit CYP1A2.

Glucocorticoids

The risk of tendon rupture is increased when administered concomitantly with glucocorticoids.

Other information

Alcohol consumption is not recommended during treatment with levofloxacin.

Special precautions for use.

The use of levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolone or fluoroquinolone-containing drugs (see section "Adverse Reactions"). Treatment of these patients with levofloxacin should be initiated only if no alternative treatment options are available and after careful assessment of benefit/risk (see section "Contraindications").

Resistance risk

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and recommended antibacterial agents for MRSA infections are considered unsuitable).

E. coli resistance

Resistance of E. coli—the most common pathogen causing urinary tract infections—to fluoroquinolones varies across all countries of the European Union. Prescribers are advised to consider local prevalence of E. coli resistance to fluoroquinolones.

Pulmonary anthrax

Clinical practice is based on in vitro susceptibility studies of Bacillus anthracis, as well as experimental data from animal studies and limited human data. Physicians should refer to national and/or international consensus guidelines for the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Rare cases of potentially irreversible serious adverse reactions have been reported following administration of quinolones or fluoroquinolones, regardless of age or existing risk factors. These reactions may lead to loss of function, persist for months or years, and affect various, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric, and sensory organs). Levofloxacin administration should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Duration of infusion

The recommended duration for infusion of Levotren infusion solution should be strictly observed: at least 30 minutes for 250 mg and at least 60 minutes for 500 mg. Tachycardia and transient decrease in blood pressure have been reported during ofloxacin infusion. Rarely, this may lead to sudden drop in blood pressure or circulatory collapse. If a marked decrease in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, the infusion should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis and tendon ruptures (including, but not limited to, Achilles tendon), sometimes bilateral, may develop within 48 hours of starting quinolone or fluoroquinolone therapy, but cases have been reported even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, organ transplant recipients, patients receiving daily doses of 1000 mg, and those receiving concomitant corticosteroid therapy. Therefore, concomitant use of levofloxacin with corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, levofloxacin therapy should be discontinued and alternative treatment considered. Appropriate management of the affected limb (e.g., immobilization) should be initiated. Corticosteroids should not be used if signs of tendinopathy are present.

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse Reactions"). The risk of developing myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent, and/or hemorrhagic, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening, with the most severe form being pseudomembranous colitis (see section "Adverse Reactions"). It is important to consider this diagnosis in patients who develop severe diarrhea during or after levofloxacin therapy. If CDAD is suspected, levofloxacin should be discontinued and appropriate treatment initiated immediately. Antiperistaltic agents are contraindicated in this clinical situation.

Patients with seizure predisposition

Quinolones may lower the seizure threshold and may provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant medications that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs, levofloxacin should be discontinued (see section "Adverse Reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions when treated with quinolone antibacterial agents. Therefore, patients receiving levofloxacin should be monitored for signs of hemolysis.

Patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (see section "Method of administration and dosage").

Hypersensitivity reactions

Levofloxacin may cause serious hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose (see section "Adverse Reactions"). In such cases, patients should discontinue treatment immediately, seek medical advice, and receive appropriate treatment.

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (also known as Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use and may be life-threatening or fatal (see section "Adverse Reactions"). Prescribers should inform patients about the signs and symptoms of severe skin reactions and monitor them closely. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. Re-administration of levofloxacin is contraindicated in patients with a history of serious reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome during prior levofloxacin therapy.

Blood glucose alterations

As with other quinolones, alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported. These events occur more frequently in elderly patients, typically in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be closely monitored in diabetic patients (see section "Adverse Reactions").

If a patient reports disturbances in blood glucose levels, treatment should be discontinued immediately and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Phototoxicity prevention

Photosensitivity reactions have been reported during levofloxacin therapy (see section "Adverse Reactions"). Patients are advised to avoid exposure to sunlight and ultraviolet (UV) radiation (e.g., UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin to prevent phototoxicity.

Patients receiving vitamin K antagonists

Due to the potential for increased coagulation test results (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these drugs are used together (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases, these reactions have progressed to suicidal thoughts and self-harming behavior, sometimes after a single dose of levofloxacin (see section "Adverse Reactions"). If such reactions occur, levofloxacin should be discontinued immediately and medical advice sought. Alternative non-fluoroquinolone antibacterial therapy should be considered, along with appropriate interventions. Levofloxacin should be used with caution in patients with a history of psychotic disorders or psychiatric illness.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage", "Overdose", and "Adverse Reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral neuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones, including levofloxacin. Patients receiving levofloxacin should be advised to inform their physician if they develop symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness; levofloxacin should be discontinued to prevent the development of potentially irreversible conditions (see section "Adverse Reactions").

Hepatobiliary disorders

Cases of hepatic necrosis up to life-threatening liver failure have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and seek medical advice if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including fatal outcomes and the need for mechanical ventilation, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for patients with a history of myasthenia gravis.

Visual disturbances

Patients should seek immediate ophthalmological evaluation if any visual disturbances occur (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse Reactions").

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection develops during treatment, appropriate measures should be taken.

Impact on laboratory test results

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate results using more specific methods may be necessary.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.

Aneurysm and dissection of the aorta and valvular regurgitation/insufficiency
Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse Reactions").

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a family history of aneurysm or congenital valvular defects, or in patients diagnosed with aortic aneurysm or dissection, valvular disease, or other risk factors or conditions predisposing to:

• aortic aneurysm and dissection, and/or valvular regurgitation/functional insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, arterial hypertension, rheumatoid arthritis), or additionally

− aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren’s syndrome), or additionally

− valvular regurgitation/functional insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and rupture is increased in patients receiving systemic corticosteroids concomitantly.

Patients should be advised to seek immediate medical attention if sudden abdominal, chest, or back pain occurs.

Patients should be instructed to seek immediate medical help if acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema occurs.

Acute pancreatitis

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the typical symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued; if confirmed, levofloxacin should not be restarted. Caution is advised in patients with a history of pancreatitis (see section "Adverse Reactions").

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during treatment with levofloxacin (see section "Adverse Reactions"). If any of these disorders are suspected, blood counts should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Important information on excipients

This medicinal product contains 15.4 mmol (or 354 mg) of sodium per 100 ml of solution, equivalent to approximately 18% of the WHO recommended maximum daily intake of sodium for adults (2 g).

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect reproductive toxicity. However, in the absence of human data and in view of experimental evidence indicating a risk of cartilage damage in the growing organism due to fluoroquinolones, levofloxacin is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding. Levofloxacin is contraindicated in breastfeeding women. There is insufficient information on the excretion of levofloxacin into breast milk. However, other fluoroquinolones are excreted into human milk. In the absence of human data and in view of experimental evidence indicating a risk of cartilage damage in the growing organism due to fluoroquinolones, levofloxacin is contraindicated in breastfeeding women (see section "Contraindications").

Fertility. Levofloxacin does not impair fertility or reproductive performance in animals.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product Levotren has a negligible or moderate effect on the ability to drive or operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and react, thus potentially posing a risk in situations where these abilities are particularly important (e.g., driving a vehicle or operating machinery).

Method of administration and dosing.

Levotren medicinal product is administered intravenously slowly once or twice daily. The dosage depends on the type and severity of infection, as well as on the susceptibility of the potential pathogen to the drug. Treatment with levofloxacin, after initial intravenous administration, may be completed with oral formulation, provided such treatment is appropriate for the individual patient. Due to the bioequivalence of parenteral and oral dosage forms, the same dose can be used.

For patients with normal renal function, in whom creatinine clearance is > 50 mL/min, the dosing is indicated in Table 3.

Table 3

Indications	Dose, mg	Number of daily doses	Treatment duration *
Community-acquired pneumonia	500	1–2 times	7–14 days
Acute pyelonephritis	500	1 time	7–10 days
Complicated urinary tract infections	500	1 time	7–14 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1–2 times	7–14 days
Pulmonary form of anthrax	500	1 time	8 weeks

* The duration of treatment includes intravenous administration and oral therapy. The time to switch from intravenous to oral treatment depends on the clinical condition, but usually ranges from 2 to 4 days.

Special patient groups

For patients with renal impairment, in whom creatinine clearance is ≤ 50 ml/min, the dosage is given in Table 4.

Table 4

Creatinine clearance	Dosing regimen (depending on infection severity and nosological form)
	250 mg/24 h	500 mg/24 h	500 mg/12 h
	initial dose – 250 mg	initial dose – 500 mg	initial dose – 500 mg
50–20 mL/min	subsequent – 125 mg/24 h	subsequent – 250 mg/24 h	subsequent – 250 mg/12 h
19–10 mL/min	subsequent – 125 mg/48 h	subsequent – 125 mg/24 h	subsequent – 125 mg/12 h
< 10 mL/min (including during hemodialysis and CRRT)1	subsequent – 125 mg/48 h	subsequent – 125 mg/24 h	subsequent – 125 mg/24 h

1After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Patients with hepatic impairment

Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.

Elderly patients

If renal function is not impaired, there is no need for dose adjustment (see section "Special precautions", namely: "Tendinitis and tendon rupture" and "QT interval prolongation").

Route of administration

Levotren medicinal product is intended for slow intravenous infusion only; it is administered once or twice daily. The infusion duration should be at least 30 minutes for 250 mg or at least 60 minutes for 500 mg of levofloxacin (see section "Special precautions").

This medicinal product is intended for single use only. The product should be used immediately after perforation of the infusion port to prevent bacterial contamination. The solution should be visually inspected before administration. Only clear solution, yellow to yellowish-green in color, practically free from particles, should be used.

Preparation for intravenous administration:

• hold the bag with the infusion port upwards;
• unscrew the protective cap from the infusion port;
• insert the medication needle into the infusion port with a rotating motion;
• hang the bag on an infusion stand.

Protection from light during infusion is not required.

As with all other medicinal products, any unused portion should be disposed of according to local regulations.

Mixing with other infusion solutions

Levotren is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose injection solution;
• 2.5% glucose in Ringer's solution;
• combined parenteral nutrition solutions (amino acids, glucose, electrolytes).

Information on incompatibilities is provided in the section "Incompatibilities".

Children.

Levofloxacin is contraindicated in children (under 18 years of age) due to the potential risk of damage to joint cartilage.

Overdose.

According to toxicity studies in animals and clinical pharmacological studies conducted with doses exceeding therapeutic levels, the most important signs of acute levofloxacin overdose are central nervous system (CNS) symptoms such as confusion, dizziness, altered consciousness, seizures, and QT interval prolongation.

In the post-marketing period, CNS adverse reactions have been observed, including confusion, convulsions, myoclonus, hallucinations, and tremor.

In case of overdose, symptomatic treatment should be administered. ECG monitoring is required due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and CAPD, is ineffective in removing levofloxacin from the body. There are no specific antidotes.

Side effects.

Adverse reactions are listed according to MedRA system organ classes and categorized by frequency:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1000, < 1/100);

rare (≥ 1/10,000, < 1/1000);

very rare (≤ 1/10,000);

not known (cannot be estimated from the available data).

Infections and infestations. Uncommon: fungal infections, including Candida species, overgrowth of other resistant microorganisms.

Blood and lymphatic system disorders. Uncommon: eosinophilia, leukopenia. Rare: neutropenia, thrombocytopenia. Not known: bone marrow depression, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders. Rare: angioedema, hypersensitivity (see section "Special precautions"). Not known: anaphylactic shock, anaphylactoid reactions (see section "Special precautions").

Metabolism and nutrition disorders. Uncommon: anorexia. Rare: hypoglycemia, especially in patients with diabetes mellitus, hypoglycemic coma (see section "Special precautions"). Not known: hyperglycemia (see section "Special precautions"). Symptoms of hypoglycemia may include increased appetite, nervousness, excessive sweating, and tremor of limbs.

Psychiatric disorders.* Common: insomnia. Uncommon: anxiety, confusion, restlessness. Rare: psychotic reactions (including hallucinations, paranoia), depression, agitation, abnormal dreams, nightmares, delirium. Not known: mania, psychotic disorders with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions").

Nervous system disorders.* Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia. Rare: seizures (see sections "Contraindications" and "Special precautions"), paraesthesia, memory impairment. Not known: myoclonus, peripheral sensory neuropathy (see section "Special precautions"), peripheral sensory motor neuropathy (see section "Special precautions"), disturbances of tactile sensation, parosmia including anosmia, dyskinesia, extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension.

Eye disorders.* Rare: visual disturbances such as blurred vision (see section "Special precautions"). Not known: transient loss of vision, uveitis (see section "Special precautions").

Ear and labyrinth disorders.* Uncommon: vertigo. Rare: tinnitus. Not known: hearing loss, disturbances of hearing.

Cardiac disorders.** Common (applies only to the intravenous formulation): phlebitis. Rare: arterial hypotension, tachycardia, palpitations. Not known: ventricular tachycardia that may lead to cardiac arrest, ventricular arrhythmia and torsade de pointes arrhythmia (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG.

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnea. Not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders. Common: diarrhea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, bloating, constipation. Not known: hemorrhagic diarrhea, which rarely may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions"), pancreatitis.

Hepatobiliary disorders. Common: increased liver enzymes (ALT/AST, alkaline phosphatase, GGT). Uncommon: increased blood bilirubin levels. Not known: jaundice and severe hepatic injury, including acute fatal liver failure, mainly in patients with severe underlying diseases (see section "Special precautions"). Hepatitis.

Endocrine disorders: Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Rare: drug rash with eosinophilia and systemic symptoms (DRESS syndrome), fixed drug eruption. Not known: skin hyperpigmentation, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, erythema multiforme exsudativum, photosensitivity reactions (see section "Special precautions"), leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders.* Uncommon: arthralgia, myalgia. Rare: tendon disorders (see sections "Contraindications" and "Special precautions"), including tendinitis (e.g., Achilles tendon), muscle weakness, particularly in patients with myasthenia gravis (see section "Special precautions"). Not known: rhabdomyolysis, tendon rupture (e.g., Achilles tendon, see sections "Contraindications" and "Special precautions"), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders. Uncommon: increased serum creatinine. Rare: acute renal failure (e.g., due to interstitial nephritis).

General disorders and administration site conditions.* Common (applies only to the intravenous formulation): infusion site reaction (pain, redness). Uncommon: asthenia. Rare: fever. Not known: pain (including back, chest, limb pain).

Other adverse reactions associated with fluoroquinolone use include acute attacks of porphyria in patients with porphyria.

*Very rare cases have been reported that lasted for several months or years, leading to disability and potentially irreversible severe adverse reactions affecting various, sometimes multiple, organ systems and sensory organs (such reactions as tendinitis, tendon rupture, limb pain, arthralgia, gait disturbance, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision and smell disturbances), and have been associated in some cases with the use of quinolones and fluoroquinolones (see section "Special precautions").

** Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been observed in patients receiving fluoroquinolones (see section "Special precautions").

aAnaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.

bSkin and mucous membrane reactions may sometimes occur even after administration of the first dose.

Other adverse reactions associated with fluoroquinolone use include acute attacks of porphyria in patients with porphyria.

Specific adverse reactions: anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances as potential aspects of prolonged and disabling fluoroquinolone-induced adverse reactions that may lead to loss of work capacity.

Reporting of suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After removal from the protective package, the shelf life is 24 hours.

Storage conditions.

Do not freeze. Store in the original packaging. This medicinal product does not require special storage conditions. Keep out of reach of children.

Incompatibilities.

This medicinal product should not be mixed simultaneously with heparin, alkaline solutions (e.g., sodium bicarbonate), or with other medicinal products except those specified in the section "Method of administration and dosage."

Packaging.

100 ml of the drug in an infusion bag within a protective pouch. 10 pouches per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

INFOMED FLUIDS S.r.l.

Manufacturer's address and place of business.

Str. Teodor Pallady nr. 50, sector 3, Bucharest, code 032266, Romania.