Leobag (Solution) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

ACS Dobfar Info S.A. (Switzerland)

ATC Code

J01MA12 (Levofloxacin)

Active Substance

Levofloxacin (Rec.INN registered by WHO)

Dosage Forms

	Leobag	Solution for infusion 5 mg/1 ml: bag 50 ml 1, 5, 10 or 20 pcs.
		Solution for infusion 5 mg/1 ml: bag 100 ml 1, 5, 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Solution for infusion from yellow to greenish-yellow, transparent.

Excipients: sodium chloride – 450 mg, water for injections – up to 50 ml, hydrochloric acid – to pH 4.8, sodium hydroxide – to pH 4.8.

50 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags made of polyester/metallized polyester/polypropylene or polyester/aluminum/polyester/polypropylene on one side and polyester ALOX/polypropylene on the other side (1) – cardboard packs.
50 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags made of polyester/metallized polyester/polypropylene or polyester/aluminum/polyester/polypropylene on one side and polyester ALOX/polypropylene on the other side (5) – cardboard packs.
50 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags made of polyester/metallized polyester/polypropylene or polyester/aluminum/polyester/polypropylene on one side and polyester ALOX/polypropylene on the other side (10) – cardboard packs.
50 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags made of polyester/metallized polyester/polypropylene or polyester/aluminum/polyester/polypropylene on one side and polyester ALOX/polypropylene on the other side (20) – cardboard packs.

Solution for infusion from yellow to greenish-yellow, transparent.

Excipients: sodium chloride – 900 mg, water for injections – up to 100 ml, hydrochloric acid – to pH 4.8, sodium hydroxide – to pH 4.8.

100 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags, made of polyester/metallized polyester/polypropylene (1) – cardboard packs.
100 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags, made of polyester/metallized polyester/polypropylene (5) – cardboard packs.
100 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags, made of polyester/metallized polyester/polypropylene (10) – cardboard packs.
100 ml – polyolefin Cryovac^® bags with multilayer connecting tube Cryovac^® (1) – forming bags, made of polyester/metallized polyester/polypropylene (20) – cardboard packs.

Clinical-Pharmacological Group

Antibacterial drug of the fluoroquinolone group

Pharmacotherapeutic Group

Antimicrobial agent – fluoroquinolone

Pharmacological Action

Levofloxacin is a broad-spectrum antimicrobial agent from the fluoroquinolone group, containing Levofloxacin as the active substance – the levorotatory isomer of ofloxacin.

It blocks DNA gyrase (topoisomerase II) and topoisomerase IV, disrupts DNA supercoiling and cross-linking of breaks, inhibits DNA synthesis, and causes profound morphological changes in the cytoplasm, cell wall, and membranes.

Levofloxacin is effective against most strains of microorganisms both in vitro and in vivo.

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum plasma concentration (C_max) or the area under the concentration-time pharmacokinetic curve and the minimum inhibitory concentration (MIC).

Mechanism of resistance

The main mechanism of resistance development is due to a mutation in the gyr-A gene.

In vitro studies show cross-resistance between levofloxacin and other fluoroquinolones.

Based on the mechanism of action, cross-antibiotic resistance between levofloxacin and other classes of antimicrobial agents is generally not observed.

The antibacterial spectrum of susceptibility of levofloxacin is presented below:

In vitro

Susceptible microorganisms (MIC ≤ 2 mg/L)

Aerobic Gram-positive microorganisms

Corynebacterium diphtheriae, Corynebacterium striatum, Enterococcus faecalis, Enterococcus spp., Listeria monocytogenes, Staphylococcus coagulase-negative methi-S (I) (coagulase-negative, methicillin-susceptible/-intermediate). Staphylococcus aureus methi-S (methicillin-susceptible strains), Staphylococcus epidermidis methi-S (methicillin-susceptible strains), Staphylococcus spp. CNS (coagulase-negative), Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae peni-I/S/R (penicillin-susceptible/-intermediate/-resistant), Streptococcus pyogenes, Streptococcus group viridans peni-S/R (penicillin-susceptible/-resistant).

Aerobic Gram-negative microorganisms

Acinetobacter baumannii, Acinetobacter spp., Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter agglomerans., Enterobacter cloacae, Enterobacter spp., Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (ampicillin-susceptible/-resistant), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella spp., Moraxella catarrhalis (beta-lactamase producing and non-producing strains), Morganella morganii, Neisseria gonorrhoeae non PPNG/PPNG (non-penicillinase producing and penicillinase producing), Neisseria meningitidis, Pasteurella canis, Pasteurella dagmatis, Pasteurella multocida, Pasteurella spp., Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Providencia spp., Pseudomonas aeruginosa, Pseudomonas spp., Salmonella spp., Serratia marcescens, Serratia spp.

Anaerobic microorganisms

Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus spp., Propionibacterium spp., Veilonella spp.

Other microorganisms

Bartonella spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp., Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma hominis, Mycoplasma pneumoniae, Ricketsia spp., Ureaplasma urealyticum.

Levofloxacin is moderately active (MIC ≥ 4 mg/L)

Aerobic Gram-positive microorganisms

Corynebacterium urealyitieum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis (methicillin-resistant), Staphylococcus haemolyticus methi-R (methicillin-resistant).

Aerobic Gram-negative microorganisms

Burkholderia cepacia, Campylobacter jejuni/coli.

Anaerobic microorganisms

Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Prevotella spp., Porphyromonas spp.

Levofloxacin is moderately active (MIC > 8 mg/L)

Aerobic Gram-positive microorganisms

Corynebacterium jeikeium, Staphylococcus aureus methi-R (methicillin-resistant), Staphylococcus coagulase-negative methi-R (methicillin-resistant).

Aerobic Gram-negative microorganisms:

Alcaligenes xylosoxidans.

Other microorganisms

Mycobacterium avium.

Nosocomial infections caused by P. aeruginosa may require combination therapy.

In vivo

The clinical efficacy of levofloxacin has been confirmed in the treatment of infections caused by the microorganisms listed below:

Aerobic Gram-positive microorganisms

Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes.

Aerobic Gram-negative microorganisms

Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens. Other

Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae

Pharmacokinetics

After intravenous (IV) infusion over 60 minutes of levofloxacin at a dose of 500 mg to healthy adult volunteers, the maximum plasma concentration averaged 6.2 µg/ml.

The pharmacokinetics of levofloxacin is linear over the dose range of 50-600 mg.

The steady-state plasma concentration of levofloxacin when administering 500 mg of levofloxacin once or twice daily is reached within 48 hours.

On day 10 of IV administration of levofloxacin 500 mg once daily, the maximum plasma concentration of levofloxacin was 6.4±0.8 µg/ml, and the minimum plasma concentration of levofloxacin (concentration before the next dose administration) was 0.6±0.2 µg/ml.

On day 10 of IV administration of levofloxacin 500 mg twice daily, the maximum plasma concentration of levofloxacin was 7.9±1.1 µg/ml, and the minimum plasma concentration of levofloxacin (concentration before the next dose administration) was 2.3±0.5 µg/ml.

Distribution

Plasma protein binding is 30-40%.

The volume of distribution of levofloxacin averages 100 L after single and multiple IV administration of 500 mg, indicating good penetration of levofloxacin into the organs and tissues of the human body.

Penetration into bronchial mucosa, epithelial lining fluid, alveolar macrophages

Levofloxacin penetrates well into the bronchial mucosa, epithelial lining fluid, and alveolar macrophages with penetration coefficients into the bronchial mucosa and epithelial lining fluid compared to plasma concentration of 1.1-1.8 and 0.8-3, respectively.

Penetration into lung tissue

Levofloxacin penetrates well into lung tissue with penetration coefficients of 2-5 compared to plasma concentration.

Penetration into alveolar fluid

Levofloxacin penetrates well into alveolar fluid with a penetration coefficient compared to plasma concentrations of 1.

When administering levofloxacin 500 mg once or twice daily for 3 days, the maximum concentrations of levofloxacin in alveolar fluid were reached 2-4 hours after administration and were 4.0 and 6.7 µg/ml, respectively.

Penetration into bone tissue

Levofloxacin penetrates well into cortical and cancellous bone tissue, both in the proximal and distal parts of the femur, with a penetration coefficient (bone tissue/plasma) of 0.1-3.

Penetration into cerebrospinal fluid

Levofloxacin poorly penetrates into the cerebrospinal fluid.

Penetration into prostate tissue

Levofloxacin penetrates well into prostate tissue (the mean prostate/plasma concentration ratio was 1.84).

Urine concentrations

High concentrations of levofloxacin are achieved in the urine, several times higher than the plasma concentrations of levofloxacin.

Metabolism

Levofloxacin is metabolized to a small extent (5% of the administered dose).

Its metabolites are demethyllevofloxacin and N-oxide Levofloxacin, which are excreted by the kidneys.

Levofloxacin is stereochemically stable and does not undergo chiral transformations.

Excretion

After IV administration, Levofloxacin is relatively slowly eliminated from plasma (half-life (T1/2) 6-8 hours).

Excretion is primarily through the kidneys (more than 85% of the administered dose).

The total clearance of levofloxacin after a single 500 mg dose is 175+29.2 ml/min.

The plasma concentration profile of levofloxacin after IV administration is similar to that after oral administration (tablets).

Therefore, the oral and IV routes of administration can be considered interchangeable.

Special patient groups

Renal impairment

The pharmacokinetics of levofloxacin depends on renal function.

In case of renal impairment, renal clearance and renal excretion of levofloxacin decrease, and T_1/2 increases according to the data in the table presented below.

Elderly patients

There are no differences in the pharmacokinetics of levofloxacin between elderly and young patients.

Exceptions are cases associated with changes in CrCl values.

Indications

Infectious and inflammatory diseases caused by microorganisms susceptible to levofloxacin

• Community-acquired pneumonia;
• Complicated urinary tract infections, including pyelonephritis;
• Uncomplicated urinary tract infections;
• Chronic bacterial prostatitis;
• Septicemia/bacteremia associated with the above indications;
• Abdominal infections;
• For complex treatment of drug-resistant forms of tuberculosis.

ICD codes

Dosage Regimen

The solution for infusion of the drug Leobag is administered slowly once or twice a day.

Doses are determined by the nature and severity of the infection, as well as the sensitivity of the suspected pathogen.

The duration of therapy depends on the type of disease and should not exceed 14 days.

In all cases, treatment should be continued for 48 to 72 hours after the disappearance of disease symptoms.

Treatment with the drug should not be interrupted independently without a doctor’s instruction.

Recommended dose of the drug for adults with normal renal function (CrCl > 50 ml/min)

For community-acquired pneumonia — 500 mg once or twice daily for 7-14 days;

For complicated urinary tract infections, including pyelonephritis — 250 mg once daily (in severe infections, the dose may be increased) for 7-10 days;

For uncomplicated urinary tract infections – 250 mg once daily for 3 days;

For chronic bacterial prostatitis – 500 mg once daily for 28 days;

For septicemia/bacteremia – 500 mg once or twice daily for 10-14 days;

For abdominal infection – 500 mg once daily for 7-14 days (in combination with antimicrobial agents active against anaerobic flora);

For complex treatment of drug-resistant forms of tuberculosis – 500 mg once or twice daily for up to 3 months.

For patients with impaired renal function (CrCl < 50 ml/min)

* After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), no additional doses are required.

Patients with impaired liver function

In case of impaired liver function, no special dose adjustment is required, since Levofloxacin is only minimally metabolized in the liver and is excreted primarily by the kidneys.

Elderly patients

No adjustment of the dosage regimen is required for elderly patients with normal renal function (see section Special Instructions).

Children and adolescents

The drug Leobag is contraindicated in children and adolescents under 18 years of age (see the Contraindications section).

The infusion solution of the drug Leobag is administered intravenously by slow drip. The duration of infusion should be at least 30 minutes for a solution containing 250 mg of levofloxacin, and at least 60 minutes for a solution containing 500 mg of levofloxacin. Depending on the patient’s condition, after several days of treatment, it is possible to switch from intravenous drip administration to oral administration of the same dose of the drug in the form intended for oral use.

The infusion solution of the drug Leobag is compatible with the following infusion solutions: 0.9% sodium chloride solution, 5% dextrose solution, 2.5% Ringer’s solution with dextrose, combined solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

The solution of the drug Leobag should not be mixed with heparin or solutions with an alkaline reaction (for example, sodium bicarbonate solution).

Directions for use

1. Perform a visual inspection of the solution before administration. The solution can only be used if it is clear, from yellow to greenish-yellow in color, without visible particles.
2. Grasp the top of the connecting tube.
3. Break off the protective tip from the connecting tube.
4. Insert the infusion system needle into the bag’s connecting tube with a screwing motion.
5. Hang the bag by the hole on the stand.

During infusion, protection of the solution from light is not required.

The solution is recommended to be used immediately; unused solution should be destroyed.

Adverse Reactions

The frequency of adverse reactions is distributed as follows:

Very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000) (including isolated reports), frequency unknown (cannot be estimated from the available data).

Infections and infestations

Uncommon – mycoses, superinfection.

Blood and lymphatic system disorders

Uncommon – leukopenia (decrease in the number of leukocytes in peripheral blood), eosinophilia (increase in the number of eosinophils in peripheral blood).

Rare – thrombocytopenia (decrease in the number of platelets in peripheral blood), neutropenia (decrease in the number of neutrophils in peripheral blood).

Frequency unknown – pancytopenia (decrease in the number of all formed elements in peripheral blood), agranulocytosis (absence or sharp decrease in the number of granulocytes in peripheral blood), hemolytic anemia.

Immune system disorders

Rare – angioedema.

Frequency unknown – hypersensitivity (see the Special Precautions section), leukocytoclastic vasculitis, anaphylactic shock (see the Special Precautions section).

Metabolism and nutrition disorders

Uncommon – anorexia.

Rare – hypoglycemia, usually in patients suffering from diabetes mellitus (possible signs of hypoglycemia: increased appetite, increased sweating, tremor) (see the Special Precautions section).

Psychiatric disorders

Common – insomnia.

Uncommon – feeling of anxiety, confusion.

Rare – psychotic disorders (e.g., with hallucinations), depression, agitation, sleep disorders, nightmares.

Frequency unknown – psychotic reactions associated with suicidal thoughts or attempts and with attempts to harm one’s own health (see the Special Precautions section).

Nervous system disorders

Common – headache, dizziness.

Uncommon – drowsiness, tremor, dysgeusia (taste perversion).

Rare – convulsions, paresthesia.

Frequency unknown – sensory or sensorimotor peripheral neuropathy; dyskinesia, extrapyramidal disorders, loss of taste; distortion of smell, including its loss.

Eye disorders

Very rare – visual impairment.

Ear and labyrinth disorders

Uncommon – vertigo.

Rare – tinnitus.

Frequency unknown – hearing impairment.

Cardiac disorders

Rare – sinus tachycardia.

Frequency unknown – QT interval prolongation (see the Special Precautions section, Overdose).

Vascular disorders

Common – phlebitis at the injection site.

Rare – decreased blood pressure.

Respiratory, thoracic and mediastinal disorders

Uncommon – dyspnea.

Frequency unknown – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders

Common – diarrhea, vomiting, nausea.

Uncommon – abdominal pain, dyspepsia.

Frequency unknown – bloody diarrhea, which in very rare cases may indicate the development of enterocolitis, including pseudomembranous colitis.

Hepatobiliary disorders

Common – increased activity of “liver” transaminases (ALT, AST, alkaline phosphatase, gamma-glutamyl transpeptidase).

Uncommon – hyperbilirubinemia.

Frequency unknown – severe liver dysfunction, including cases of acute liver failure (see the Special Precautions section).

Skin and subcutaneous tissue disorders

Uncommon – rash, pruritus, urticaria.

Frequency unknown – toxic epidermal necrolysis (Lyell’s syndrome), malignant exudative erythema (Stevens-Johnson syndrome), exudative multiforme erythema, photosensitivity reactions. Reactions on the mucous membrane may sometimes occur after the first dose of the drug.

Musculoskeletal and connective tissue disorders

Uncommon – arthralgia, myalgia.

Rare – tendon disorders (see the Special Precautions section), including tendinitis, muscle weakness which may be of particular importance for patients with myasthenia gravis.

Frequency unknown – rhabdomyolysis, tendon rupture. This side effect may develop within 48 hours after the start of therapy and may be noted bilaterally.

Renal and urinary disorders

Uncommon – increased blood creatinine.

Rare – acute renal failure (e.g., due to the development of interstitial nephritis).

General disorders and administration site conditions

Common – reactions at the injection site (pain, skin hyperemia).

Uncommon – asthenia.

Rare – hyperthermia.

Other side effects that may be associated with the use of fluoroquinolones porphyria attacks in patients with porphyria.

Contraindications

• Hypersensitivity to levofloxacin or other quinolones, as well as to excipients of the drug;
• Epilepsy;
• Tendon damage during previous treatment with fluoroquinolones;
• Childhood and adolescence (up to 18 years);
• Pregnancy;
• Lactation period.

With caution

• In patients predisposed to the development of seizures (with a history of brain damage (stroke or severe trauma), in patients simultaneously receiving drugs that lower the seizure threshold of the brain (fenbufen, theophylline);
• Glucose-6-phosphate dehydrogenase deficiency;
• Impaired renal function;
• In patients with a predisposition to QT interval prolongation: elderly age, with electrolyte imbalance (e.g., hypokalemia, hypomagnesemia); congenital QT interval prolongation; with heart failure, myocardial infarction, bradycardia; with simultaneous use of drugs that prolong the QT interval (class IA and III antiarrhythmic drugs, tricyclic antidepressants, antipsychotic drugs, tetracyclic antidepressants, neuroleptics, antifungal drugs, imidazole derivatives, some antihistamines (including astemizole, terfenadine, ebastine), macrolides);
• In patients with diabetes mellitus receiving oral hypoglycemic agents (e.g., glibenclamide) or insulin (risk of hypoglycemia).
• In patients with severe adverse reactions to other fluoroquinolones, such as severe neurological reactions (increased risk of similar reactions when using levofloxacin).
• Myasthenia gravis.

Use in Pregnancy and Lactation

The drug Leobag should not be used in pregnant and lactating women, since there is a risk of damage to the cartilage tissue of the fetus and child.

Use in Hepatic Impairment

There have been reports of the development of liver necrosis up to the development of life-threatening liver failure. These phenomena were observed primarily in patients with a severe course of any disease (e.g., sepsis). If symptoms of liver disease such as: anorexia, jaundice, dark urine, itching or abdominal pain are detected, the patient should consult a doctor.

Use in Renal Impairment

Since Levofloxacin is excreted primarily by the kidneys, in patients with impaired renal function, dose adjustment and monitoring of renal function are required.

Pediatric Use

The drug Leobag is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required for elderly patients with normal renal function. When treating elderly patients, it should be taken into account that patients in this age group may have reduced renal function.

Special Precautions

Leobag should not be used to treat children and adolescents due to the likelihood of damage to the articular cartilage.

When treating elderly patients, it should be taken into account that patients in this age group may have reduced renal function.

In severe pneumonia caused by Streptococcus pneumoniae, Leobag may not provide an optimal therapeutic effect.

Hospital infections caused by certain pathogens (P.aeruginosa) may require combination therapy.

Infusion duration

The recommended duration of intravenous infusion should be at least 30 minutes for a solution containing 250 mg, and at least 60 minutes for a solution containing 500 mg of levofloxacin. Experience with levofloxacin shows that during infusions, increased heartbeat and transient decrease in blood pressure may be observed. In rare cases, a transient decrease in blood pressure can cause vascular collapse. If a pronounced decrease in blood pressure is observed during levofloxacin infusions, the infusion should be stopped immediately. For sterility reasons, it is recommended to administer the solution immediately after opening the package. Before use, it is recommended to check the solution visually for the presence of visible particles. Only a clear solution without visible particles can be used. The remaining amount of the solution should be discarded.

Methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant strains of S. aureus are most likely to have cross-resistance to fluoroquinolones, including Levofloxacin. Therefore, treatment with levofloxacin is not recommended in case of suspicion or confirmed disease caused by MRSA until the sensitivity of the microorganism to levofloxacin is confirmed.

Tendinitis and tendon rupture

In rare cases, tendinitis may develop with the administration of the drug Leobag. Tendinitis (primarily inflammation of the Achilles tendon) that developed during the use of the drug can lead to tendon rupture. Elderly patients and patients taking glucocorticosteroids are most predisposed to the development of tendinitis. When administering the drug to this group of patients, their condition should be carefully monitored. Patients should inform the attending physician about the appearance of symptoms of tendinitis. If tendinitis is suspected, treatment with Leobag should be stopped immediately and appropriate treatment of the affected tendon should be started, for example, by ensuring its rest (see the Contraindications and Adverse Reactions sections).

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent form with blood, occurring during or after administration of the drug, may be a sign of a disease caused by Clostridium difficile. The most severe form of this disease is pseudomembranous colitis. If pseudomembranous colitis is suspected, the administration of the drug Leobag should be stopped immediately and specific antibiotic therapy (e.g., oral vancomycin) should be started immediately. In this case, drugs that inhibit intestinal motility should not be used.

Patients predisposed to seizures

It should be borne in mind that in patients with a history of brain damage (stroke, severe traumatic brain injury, epilepsy), seizures may develop. Caution should also be exercised when co-administering the drug Leobag and drugs that lower the seizure threshold (see the Drug Interactions section). If seizures develop, the administration of the drug Leobag should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

In case of glucose-6-phosphate dehydrogenase deficiency, there is a risk of hemolysis during treatment with quinolones.

Patients with impaired renal function

Since Levofloxacin is excreted primarily by the kidneys, in patients with impaired renal function, dose adjustment (see the Dosage and Administration section) and monitoring of renal function are required.

Hypersensitivity reactions

Levofloxacin can cause severe, life-threatening hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) immediately after the first administration. In case of development of these reactions, treatment with the drug Leobag should be stopped immediately and appropriate therapy should be started.

Hypoglycemia

As a rule, during treatment with quinolones, hypoglycemia develops in patients suffering from diabetes mellitus and taking oral hypoglycemic agents (e.g., glibenclamide) or insulin injections. In this group of patients, blood glucose concentration should be carefully monitored (see the Adverse Reactions section).

Prevention of photosensitivity reactions

Although cases of photosensitivity reactions during levofloxacin administration are very rare, it is necessary to avoid solar and artificial ultraviolet radiation (solarium) to avoid damage to the skin (photosensitization).

Patients taking indirect anticoagulants, coumarin derivatives

An increase in coagulation test values (prothrombin time/international normalized ratio) and/or an increase in bleeding time is possible in patients taking indirect anticoagulants, coumarin derivatives (e.g., warfarin) together with levofloxacin. Blood coagulation should be monitored in this group of patients.

Psychotic reactions

In patients taking quinolones, including Levofloxacin, the development of psychotic reactions is possible. In very rare cases, even after the first dose of levofloxacin, these reactions can turn into suicidal thoughts and behavior aimed at harming one’s own health (see the Adverse Reactions section). In case of the appearance of the reactions described above, the administration of the drug Leobag should be discontinued and appropriate measures should be taken. It should be used with caution when prescribed to patients with psychotic disorders or patients with a history of psychiatric diseases.

QT interval prolongation

It should be used with caution in patients with risk factors for QT interval prolongation

• Congenital QT interval prolongation.

• Simultaneous use of drugs that prolong the QT interval (e.g., class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotic drugs, tetracyclic antidepressants, neuroleptics, antifungal drugs, imidazole derivatives, some antihistamines (including astemizole, terfenadine, ebastine)).

• Electrolyte imbalance (e.g., hypokalemia, hypomagnesemia).

• Elderly patients.

• Heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Peripheral neuropathy

There have been reports of the development of sensory or sensorimotor peripheral neuropathy when taking fluoroquinolones, including when taking levofloxacin, the symptoms of which develop rapidly. If a patient develops symptoms of neuropathy, the administration of the drug Leobag should be discontinued in order to prevent the development of an irreversible condition of the disease.

Opiates

Levofloxacin may give a false-positive result for opiates determined in urine using immunological test systems. In this regard, during treatment with levofloxacin, it is necessary to use more specific methods of analysis for opiates.

Disorders of the liver and biliary tract

There have been reports of the development of liver necrosis up to the development of life-threatening liver failure. These phenomena were observed primarily in patients with a severe course of any disease (e.g., sepsis) (see the Adverse Reactions section). If symptoms of liver disease such as: anorexia, jaundice, dark urine, itching or abdominal pain are detected, the patient should consult a doctor.

Other precautions

The sodium content in the drug is about 154 µmol/ml (3.54 mg/ml). This should be taken into account in patients on a sodium diet and in cases where fluid intake is limited.

Effect on ability to drive and operate machinery

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Expected symptoms of an overdose of the drug Leobag are manifested at the level of the central nervous system (confusion, dizziness, impaired consciousness and convulsive seizures of the epileptic type). In addition, gastrointestinal disorders (e.g., nausea) and erosive lesions of the mucous membranes may be noted. From the cardiovascular system, QT interval prolongation may be observed.

Treatment is symptomatic. ECG monitoring is necessary to track the QT interval. Levofloxacin is not removed by dialysis. There is no specific antidote.

Drug Interactions

There are reports of a pronounced decrease in the seizure threshold with the simultaneous use of quinolones and substances that can, in turn, lower the seizure threshold. This equally applies to the simultaneous use of quinolones, theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs. It was noted that the concentration of levofloxacin is approximately 13% higher in the presence of fenbufen compared to the values during monotherapy.

No effect on the pharmacokinetics of levofloxacin from calcium carbonate, digoxin, glibenclamide and ranitidine was identified.

The use of glucocorticosteroids increases the risk of tendon rupture.

With simultaneous use of indirect anticoagulants, coumarin derivatives, monitoring of the blood coagulation system is necessary due to the possible development of severe bleeding. The excretion (renal clearance) of levofloxacin is slowed down under the influence of cimetidine (by 24%) and probenecid (by 34%) due to the possible blocking of tubular secretion of levofloxacin in the kidneys. It should be noted that this interaction is of clinical importance primarily for patients with impaired renal function. Simultaneous administration of levofloxacin and drugs that block tubular secretion should be carried out with caution, especially in patients with impaired renal function.

Levofloxacin increases the T_1/2 of cyclosporine by 33%. Since this increase is clinically insignificant, no dose adjustment of cyclosporine is required when it is used concomitantly with levofloxacin.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients taking drugs that prolong the QT interval (for example, class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics, tetracyclic antidepressants, neuroleptics, antifungal drugs, imidazole derivatives, some antihistamines (including astemizole, terfenadine, ebastine)).

When levofloxacin and hypoglycemic agents are used concomitantly, changes in blood glucose levels are observed; for this reason, it is recommended to monitor blood glucose levels during concomitant use of this group of drugs.

The Leobag infusion solution is compatible with 0.9% sodium chloride solution, 5% dextrose solution, 2.5% Ringer’s solution with dextrose, and combined solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

It must not be mixed with heparin and solutions having an alkaline reaction (for example, sodium bicarbonate solution).

The Leobag drug solution must not be mixed with other medicinal products.

Storage Conditions

Store in the original packaging, in a place protected from light, at a temperature not exceeding 25°C (77°F). After removal from the mold-forming bag, the solution can be stored for no more than 7 days! Keep out of reach of children!

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.