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

Composition:

Active substance: levofloxacin;

1 vial contains levofloxacin hemihydrate equivalent to levofloxacin 500 mg;

1 ml of solution contains levofloxacin hemihydrate equivalent to levofloxacin 5 mg;

Excipients: sodium chloride, edetate disodium, hydrochloric acid diluted, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear green-yellow solution.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group and the S-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action.

The fluoroquinolone-group antibacterial agent levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship.

The extent of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (C_max) or the area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC).

Mechanism of resistance.

Resistance to levofloxacin develops through stepwise mutations in the target site of both types of topoisomerase II: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability (particularly relevant for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance is observed between levofloxacin and other fluoroquinolones. Due to its mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints.

The breakpoints for MIC of levofloxacin recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which differentiate susceptible microorganisms from those with intermediate susceptibility (moderately resistant) and intermediate-susceptible from resistant organisms, are presented in the MIC testing table below (mg/L).

EUCAST clinical breakpoints for levofloxacin (version 2.0, 01.01.2012):

Table 1

Pathogens	Susceptible	Resistant
Enterobacteriaceae	≤ 1 mg/l	> 2 mg/l
Pseudomonas spp.	≤ 1 mg/l	> 2 mg/l
Acinetobacter spp.	≤ 1 mg/l	> 2 mg/l
Staphylococcus spp.	≤ 1 mg/l	> 2 mg/l
S. pneumoniae 1	≤ 2 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 1 mg/l	> 2 mg/l
H. influenzae 2,3	≤ 1 mg/l	> 1 mg/l
M. catarrhalis 3	> 1 mg/l	> 1 mg/l
Species-independent breakpoints 4	≤ 1 mg/l	> 2 mg/l

1 Breakpoint values for levofloxacin apply to high-dose therapy.

2 A low level of resistance to fluoroquinolones may be possible (MIC of ciprofloxacin 0.12–0.5 mg/L), but there is no evidence that such resistance has clinical significance in respiratory tract infections caused by H. influenzae.

3 Strains with MIC values above the breakpoint between susceptible and intermediate (moderately resistant) strains are very rare or have not yet been reported. Susceptibility testing on any such isolate should be repeated, and if confirmed, the isolate should be sent to a reference laboratory. As long as data indicating clinical response for confirmed isolates with MIC above the current resistant breakpoint are lacking, such isolates must be reported as resistant.

4 Breakpoint values for oral doses ranging from 500 mg once daily to 500 mg twice daily and intravenous doses ranging from 500 mg once daily to 500 mg twice daily.

The prevalence of resistance may vary geographically and over time for individual species, and it is advisable to obtain local resistance data, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the utility of the drug at least questionable 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 parainfluenzae, 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 for which acquired (secondary) resistance may be problematic.

Aerobic Gram-positive bacteria.

Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Staphylococcus coagulase 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.

Gram-positive aerobes:

Enterococcus faecium.

* Methicillin-resistant S. aureus may exhibit resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

When administered orally, levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations are reached within 1–2 hours after administration. Absolute bioavailability is 99–100%. Food has a minor effect on its absorption. Steady-state levels are achieved within 48 hours after administration of 500 mg once or twice daily.

Distribution.

Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacin is about 100 L after single and repeated 500 mg doses, indicating good tissue penetration throughout the body.

Penetration into tissues and body fluids.

Levofloxacin has been shown to penetrate into bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (vesicle contents), prostate tissue, and urine. Levofloxacin penetrates poorly into cerebrospinal fluid.

Metabolism.

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

Elimination.

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose).

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 after intravenous and oral administration, indicating that these routes (oral and intravenous) are interchangeable.

Linearity.

Levofloxacin follows linear pharmacokinetics in the range of 50–1000 mg.

Special populations.

Patients with renal impairment.

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

Pharmacokinetics in renal impairment after a single 500 mg oral dose.

Table 2

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

Elderly 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 female and male 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.

Levsan, infusion solution, is indicated for the treatment of the following infectious diseases in adults:

community-acquired pneumonia;
complicated skin and soft tissue infections;

(for the above-mentioned infectious diseases, levofloxacin should be prescribed only when other antibacterial medicinal products primarily used for initial treatment of these infections are insufficiently effective);

pyelonephritis and complicated urinary tract infections;
chronic bacterial prostatitis;
pulmonary form of anthrax: post-exposure prophylaxis and definitive treatment.

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

Contraindications.

Levsan must not be administered in the following cases:

hypersensitivity to levofloxacin or to other quinolones or to any of the other components of the medicinal product;
adverse reactions affecting tendons following previous administration of quinolones;
epilepsy;
childhood (under 18 years of age);
pregnancy or breastfeeding.

Special safety precautions.

Levsan for intravenous administration should be used immediately (within 3 hours) after perforation of the rubber stopper. Protection from light during infusion is not required.

Under room lighting conditions, the intravenous solution may be stored for up to 3 days without protection from light. The medicinal product is intended for single use only. The solution should be inspected before use. Only clear green-yellow solution free from particles should be used.

As with all other medicinal products, any unused medicinal product should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on Levsan.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory medicinal products.

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, nonsteroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.

Probenecid and cimetidine.

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both drugs are capable of blocking tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical significance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be done with caution, especially in patients with renal impairment.

Other information.

Clinical pharmacology studies have demonstrated that no clinically significant effect on the pharmacokinetics of levofloxacin occurs when levofloxacin is administered with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of Levsan on other medicinal products.

Cyclosporine.

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

Vitamin K antagonists.

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (PT/INR) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving vitamin K antagonists concurrently should have coagulation parameters monitored (see section "Dosage and administration").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) (see section "Dosage and administration" (QT interval prolongation)).

Other significant information.

Levofloxacin does not affect the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme), indicating that levofloxacin is not an inhibitor of CYP1A2.

Special precautions for use.

Duration of infusion.

The recommended duration of infusion is at least 30 minutes for 250 mg or 60 minutes for 500 mg of the Levsan infusion solution. With regard to ofloxacin, tachycardia and transient increase in blood pressure may occur during infusion. In rare cases, a consequent sharp drop in blood pressure or circulatory collapse may be observed. If marked hypotension occurs during infusion of levofloxacin (l- isomer of ofloxacin), the infusion should be immediately discontinued.

Methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus is very likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of known or suspected MRSA infections, except when laboratory test results confirm susceptibility of the pathogen to levofloxacin.

Resistance of E. coli.

Resistance of E. coli, the most common pathogen in urinary tract infections, to fluoroquinolones varies across countries of the European Union. When prescribing levofloxacin, physicians should take into account the local prevalence of E. coli resistance to fluoroquinolones.

Pulmonary form of anthrax.

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

Sodium.

This medicinal product contains 39.1 mmol (900 mg) of sodium per 100 ml of solution. This should be taken into consideration for patients on a sodium-controlled diet.

Tendinitis and tendon rupture.

Tendonitis may rarely occur. It most commonly affects the Achilles tendon and may lead to tendon rupture. Tendinitis and tendon ruptures, sometimes bilateral, may occur within 48 hours after administration of levofloxacin and even several months after discontinuation of levofloxacin. Patients over 60 years of age, those receiving a daily dose of 1000 mg of levofloxacin, and patients treated with corticosteroids are at higher risk. Patients who have undergone organ transplantation have an increased risk of tendinitis; therefore, fluoroquinolones should be used with caution in this population. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section "Dosage and administration"). Elderly patients receiving levofloxacin should be monitored. Patients should consult a physician if symptoms of tendinitis occur. If tendinitis is suspected, treatment with Levsan should be immediately discontinued and appropriate management initiated (e.g., immobilization of the tendon).

Myoclonus.

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

Clostridium difficile-associated disease.

Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after treatment with Levsan (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. The severity of CDAD ranges from mild to life-threatening. This diagnosis should be considered in patients who develop severe diarrhea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, infusion of Levsan should be immediately discontinued and appropriate treatment initiated promptly. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures.

Quinolones may lower the seizure threshold and provoke seizures. The Levsan infusion solution is contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, such as those with prior central nervous system disorders or those receiving concomitant medications that lower the cerebral seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, treatment with levofloxacin should be discontinued.

Blood disorders.

Treatment with levofloxacin may lead to bone marrow dysfunction, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (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.

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 during treatment with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients, and monitoring for possible hemolysis is recommended.

Patients with renal impairment.

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

Hypersensitivity reactions.

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

Severe bullous reactions.

Severe bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported with levofloxacin (see section "Adverse reactions"). If skin and/or mucosal reactions occur, patients should consult a physician before continuing treatment.

Disglycemia.

As with all quinolones, fluctuations in blood glucose levels, including hyperglycemia and hypoglycemia, have been reported, particularly in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

Phototoxicity prevention.

Although phototoxicity is very rare with levofloxacin, patients are advised to avoid exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during and for 48 hours after treatment with levofloxacin to prevent such reactions.

Patients receiving vitamin K antagonists.

Due to possible increases in coagulation test parameters (PT/INR) and/or bleeding in patients taking Levsan in combination with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored when these medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of 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 women may be more sensitive to medicinal products that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Dosage and administration," "Elderly patients," "Interaction with other medicinal products and other forms of interaction," "Adverse reactions," "Overdose").

Peripheral neuropathy.

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including levofloxacin, and may develop rapidly. Levofloxacin should be discontinued if symptoms of neuropathy occur to prevent irreversible damage.

Hepatobiliary disorders.

Cases of necrotizing hepatitis, 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, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal outcomes and the need for respiratory support, have been reported during the post-marketing period in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If visual disturbances or other ocular effects occur, patients should immediately consult an ophthalmologist (see sections "Adverse reactions," "Effect on ability to drive and use machines").

Superinfection.

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

Effect on laboratory tests.

In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate test results by more specific methods may be necessary. Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative bacteriological test results in patients with tuberculosis.

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 harmful effects on reproductive toxicity. Due to the lack of human studies and the potential for quinolones to damage developing joint cartilage, Levsan should not be administered to pregnant women or women who are breastfeeding. If pregnancy is diagnosed during treatment with Levsan, the physician should be informed.

Breastfeeding.

Levsan is contraindicated during breastfeeding. Information on the passage of levofloxacin into breast milk is limited, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage developing joint cartilage, levofloxacin should not be administered to women who are breastfeeding.

Fertility.

Levsan did not cause disorders of fertility or reproductive function in rats.

Effect on ability to drive and use machines.

Patients who drive vehicles or operate machinery should be aware of possible adverse reactions affecting the nervous system (dizziness, paresthesia, somnolence, confusion, visual and hearing disturbances, motor disturbances, including during walking).

Method of administration and dosage.

A sensitivity test should be performed before administration.

The drug should be administered intravenously slowly once or twice daily. Dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the drug.

Transition from initial intravenous administration of levofloxacin to appropriate oral administration is possible according to the instructions for medical use of the drug in the form of film-coated tablets, depending on the patient's condition. Considering the bioequivalence of oral and parenteral forms, the dosage may be the same.

For treatment of patients with normal renal function, in whom creatinine clearance is over 50 mL/min, the following doses are usually recommended:

Table 3

Indications	Daily dose	Total duration of treatment1
Indications	(depending on severity)
Community-acquired pneumonia	500 mg once or twice daily	7–14 days
Pyelonephritis	500 mg once daily	7–10 days
Complicated urinary tract infections	500 mg once daily	7–14 days
Chronic bacterial prostatitis	500 mg once daily	28 days
Complicated skin and soft tissue infections	500 mg once or twice daily	7–14 days
Pulmonary form of anthrax	500 mg once daily	8 weeks

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

Special populations

Dosing for patients with impaired renal function with a creatinine clearance of less than 50 ml/min:

Table 4

Creatinine clearance

Dosing regimen

(depending on the severity of infection and nosological form)

250 mg/24 hours

500 mg/24 hours

500 mg/12 hours

50–20 mL/min

initial dose – 250 mg;
subsequent –

125 mg/24 hours