Levoaar iv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOAAR IV

Composition:

Active substance: levofloxacin;

100 ml of solution contain levofloxacin hemihydrate equivalent to 500 mg of levofloxacin;
Excipients: anhydrous glucose, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear greenish-yellow solution.

Pharmacotherapeutic group.
Antibacterials for systemic use. Quinolone antibacterials. Fluoroquinolones. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action. As an antibacterial agent of the fluoroquinolone group, 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 maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance. The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, 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.

Clinical breakpoints

The recommended breakpoints for levofloxacin MIC values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from intermediate (moderately resistant) organisms, and intermediate from resistant organisms, are presented in Table 1 of MIC testing (mg/l).

Clinical MIC breakpoints for levofloxacin (version 10.0, 01-01-2020)

Table 1

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 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
Staphylococcus spp.	≤ 1 mg/l	> 2 mg/l
S. pneumoniae	≤ 0.001 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 0.001 mg/l	> 2 mg/l
H. influenzae	≤ 0.06 mg/l	> 0.06 mg/l
M. 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
Species-unrelated breakpoints	≤ 0.5 mg/l	> 1 mg/l

1 Only uncomplicated urinary tract infections.

2Susceptibility conclusion can be drawn based on susceptibility to ciprofloxacin.

Resistance prevalence may vary geographically and over time for individual species, and it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, advice from a specialist should be sought when local resistance prevalence is such that the benefit of the drug, at least for some types of infections, is questionable.

Typically 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 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.

After oral administration, levofloxacin is rapidly and almost completely absorbed, reaching maximum plasma concentration within 1–2 hours. Absolute bioavailability is approximately 99–100%.

Food has almost no effect on the absorption of levofloxacin.

Steady state is achieved within 48 hours with a dosing regimen 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 extensive tissue distribution throughout the body.

Penetration into tissues and body fluids.

Levofloxacin has the ability to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation.

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

Elimination.

After 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). The mean total 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 interchangeability of these routes (oral and intravenous).

Linearity.

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

Special populations

Patients with renal impairment.

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance are decreased, and elimination half-lives are prolonged, as shown in the table below (Table 2):

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

Geriatric patients.

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

Gender differences.

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

Clinical characteristics.

Indications.

The medicinal product Levooar IV is indicated in adults for the treatment of infections caused by microorganisms sensitive to the drug (see sections "Pharmacodynamics", "Special precautions for use"), such as:

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

(For the above-mentioned infections, the drug should be prescribed only when the use of other antibacterial agents, which are usually recommended for initial treatment of these infections, is inappropriate or impossible);

• 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").

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

Contraindications.

Hypersensitivity to levofloxacin, other fluoroquinolones, or to any of the excipients of the medicinal product. Epilepsy. History of tendon-related adverse reactions following previous administration of quinolones. Pregnancy or breastfeeding. Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs).

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones together with theophylline and nonsteroidal anti-inflammatory drugs or other agents that lower the seizure threshold. Levofloxacin concentrations are approximately 13% higher in the presence of fenbufen compared to levofloxacin 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% with probenecid. This is because both drugs can block tubular secretion of levofloxacin. However, at the doses tested in studies, it is unlikely that statistically significant kinetic differences would have clinical relevance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Cyclosporine.

The 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 parameters (prothrombin time/international normalized ratio) and/or bleeding events, 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 prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic medicinal products) (see section "Special precautions for use" (QT interval prolongation)).

Theophylline.

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2; therefore, levofloxacin is not considered an inhibitor of CYP1A2.

Glucocorticoids.

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

Others.

No clinically significant effect on the pharmacokinetics of levofloxacin was observed when administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine. Concomitant use of levofloxacin with alcohol is not recommended.

Special precautions for use.

The use of this drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with levofloxacin should be initiated in such patients only if no alternative treatment options are available and after careful assessment of benefit/risk (see also section "Contraindications").

Resistance risk

For methicillin-resistant S. aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and when standard antibacterial agents for MRSA infections are considered inappropriate).

Resistance to fluoroquinolones in E. coli (the most common cause of urinary tract infections) varies across countries. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.

Pulmonary form of anthrax

Pulmonary anthrax: the use of the drug for treatment in humans is based on in vitro data on susceptibility of Bacillus anthracis, experimental animal data, 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, prolonged (several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous and psychiatric systems, sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or presence of risk factors. At the first signs or symptoms of any serious adverse reaction, levofloxacin should be discontinued immediately and medical advice sought.

Duration of infusion

The recommended duration of infusion should be at least 30 minutes for 250 mg or 60 minutes for 500 mg of levofloxacin infusion solution. Tachycardia and transient decrease in blood pressure have been reported during ofloxacin infusion. Rarely, severe hypotension may lead to cardiovascular failure. If a significant drop in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, administration of the drug should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours after initiation of treatment with quinolones or fluoroquinolones, and even several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided. At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

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 levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately and appropriate treatment initiated at the first occurrence of myoclonus.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, and/or bloody, occurring during or after levofloxacin treatment (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The most severe form of this condition is pseudomembranous colitis (see section "Adverse Reactions"). The severity of Clostridium difficile-associated diseases ranges from mild to life-threatening, with pseudomembranous colitis being the most severe form (see section "Adverse Reactions"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after levofloxacin treatment. If Clostridium difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated urgently. Medicinal products that inhibit intestinal motility are contraindicated in this case.

Patients with seizure predisposition

Quinolones may lower the seizure threshold and 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 (see section "Adverse Reactions"), levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis should be performed.

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 (including angioedema, anaphylactic shock), even after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin reactions

Severe skin reactions, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse Reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of such reactions occur, levofloxacin treatment should be stopped immediately and alternative therapy considered. Patients who have experienced Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS during levofloxacin treatment must not be re-exposed to levofloxacin under any circumstances.

Blood glucose alterations

Alterations in blood glucose levels (hyperglycemia and hypoglycemia) have been reported in elderly patients, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin, during treatment with quinolones. Cases of hypoglycemic coma have been observed. Blood glucose monitoring is required in diabetic patients (see section "Adverse Reactions").

Levofloxacin treatment should be discontinued immediately if blood glucose disturbances occur, and alternative antibacterial therapy not containing fluoroquinolones should be considered.

Prevention of photosensitivity reaction

Cases of photosensitivity have been reported during levofloxacin use (see section "Adverse Reactions"). Patients taking levofloxacin should avoid exposure to intense sunlight and ultraviolet radiation (UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of the drug to prevent photosensitivity.

Patients receiving vitamin K antagonists

Due to the possible increase in coagulation parameters (prothrombin time/international normalized ratio [INR]) and/or bleeding in patients receiving levofloxacin in combination with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychiatric reactions

Psychiatric reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-harming 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. Alternative antibacterial therapy not containing fluoroquinolones should be considered. Levofloxacin should be used cautiously in patients with psychiatric 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 or acquired long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• electrolyte imbalances (particularly hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and 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 "Dosage and administration (Elderly patients)", "Interaction with other medicinal products and other forms of interaction", "Adverse Reactions", "Overdose").

Aortic aneurysm and dissection, 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/insufficiency 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:

• positive family history of aneurysmal disease or congenital valvular disease, or diagnosed aortic aneurysm and/or aortic dissection or valvular disease, or
• risk factors or conditions predisposing to:
  • aortic aneurysm and dissection and valvular regurgitation/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, known atherosclerosis, Sjögren's syndrome), or additionally:
• valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm and dissection and their rupture may also be increased in patients receiving concomitant systemic corticosteroids.

Patients should be advised to seek immediate medical attention in case of sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical attention if acute dyspnea, new onset of rapid heartbeat, 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 should be exercised in patients with a history of pancreatitis (see section "Adverse Reactions").

Blood disorders

Bone marrow dysfunction, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during levofloxacin treatment (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.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician promptly to prevent progression to potentially irreversible conditions (see section "Adverse Reactions").

Hepatobiliary disorders

Cases of liver necrosis up to liver failure with fatal outcome have been reported during levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions including fatalities and conditions requiring respiratory support have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or ocular adverse reactions occur during levofloxacin treatment, patients should seek immediate ophthalmological consultation (see sections "Adverse Reactions" and "Effect on ability to drive and use machines").

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of organisms not susceptible (resistant) to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Excipients

The drug contains 5 g of glucose per dose (100 ml vial). Therefore, caution is advised when administering to patients with diabetes mellitus.

This medicinal product contains less than 1 mmol (23 mg)/dose (100 ml vial) of sodium, i.e., essentially "sodium-free".

Effect on laboratory test results

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

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and thus lead to false-negative results in bacteriological diagnosis of 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 reproductive toxicity (see section "Pharmacological properties"). However, due to the lack of human data and experimental evidence indicating a risk of cartilage damage in the growing organism from fluoroquinolones, the drug is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding. Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the passage of levofloxacin into breast milk, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage joint cartilage in the growing organism, the drug is contraindicated during breastfeeding (see sections "Contraindications" and "Pharmacological properties").

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

Effect on ability to drive and use machines

Levofloxacin has a minor or moderate effect on the ability to drive and use machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving or operating machinery).

Administration and Dosage

Prior to administration, a sensitivity test must be performed.

Levofloxacin solution should be administered by slow intravenous infusion once or twice daily. The dose depends on the type and severity of infection and on the susceptibility of the causative organism. After several days of treatment, if the patient's condition permits, the initial intravenous administration may be switched to oral administration (levofloxacin tablets 250 mg or 500 mg). Due to the bioequivalence of the parenteral and oral formulations, the same dosage may be used. The duration of treatment depends on the course of the disease. Administration of the drug should be continued for at least 48–72 hours after the disappearance of clinical signs of infection. Levofloxacin for infusion is intended for slow intravenous administration only and should be given once or twice daily. The infusion time should be no less than 30 minutes for the 250 mg dose and no less than 60 minutes for the 500 mg dose.

Table 3

Recommended doses of the drug for the treatment of adults with normal renal function, in whom creatinine clearance is over 50 mL/min

Indications	Dose, mg	Number of doses per day (by severity)	Treatment duration* (by severity)
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

* Duration of treatment includes both intravenous and oral administration of the medicinal product. The time of transition from intravenous to oral administration depends on the clinical condition, but usually takes from 2 to 4 days.

Table 4

Dosage for adult patients with renal impairment, in whom creatinine clearance is less than 50 ml/min

Dosing regimen
Creatinine clearance	250 mg/24 hours	500 mg/24 hours	500 mg/12 hours
50–20 mL/min	initial dose – 250 mg subsequent – 125 mg/24 h	initial dose – 500 mg subsequent – 250 mg/24 h	initial dose – 500 mg subsequent – 250 mg/12 h
19–10 mL/min	initial dose – 250 mg subsequent – 125 mg/48 h	initial dose – 500 mg subsequent – 125 mg/24 h	initial dose – 500 mg subsequent – 125 mg/12 h
< 10 mL/min (as well as during hemodialysis and CAPD1)	initial dose – 250 mg subsequent – 125 mg/48 h	initial dose – 500 mg subsequent – 125 mg/24 h	initial dose – 500 mg subsequent – 125 mg/24 h

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

Dosage in patients with hepatic impairment

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

Dosage in elderly patients

If renal function is not impaired, there is no need for dose adjustment (see section "Special precautions").

Administration method

Levofloxacin must be administered slowly by intravenous infusion. The duration of infusion of one vial (100 mL of solution for intravenous infusion containing 500 mg of levofloxacin) should be no less than 60 minutes for the 500 mg dose; the recommended infusion rate for the 250 mg dose is 30 minutes.

The duration of treatment depends on the course of the disease. As with other antibacterial agents, treatment with Levopro should be continued for at least 48–72 hours after normalization of body temperature or until microbiological eradication of the causative organism has been confirmed.

Children

The medicinal product is contraindicated in children and adolescents (under 18 years of age) (see section "Contraindications").

Overdose

According to toxicity studies in animals and clinical pharmacological studies using doses exceeding the therapeutic dose, the most important expected symptoms of levofloxacin overdose involve the central nervous system (CNS) and include confusion and altered consciousness, dizziness, seizures, hallucinations, tremor, and QT interval prolongation.

During post-marketing surveillance, CNS adverse reactions such as confusion, seizures, hallucinations, and tremor have been observed.

In case of overdose, symptomatic therapy should be administered according to clinical manifestations. In cases of overdose, careful patient monitoring, including ECG monitoring due to the potential for QT interval prolongation, is required. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

CNS effects, including confusion, seizures, myoclonus, hallucinations, and tremor, have been observed in the post-marketing period.

Adverse reactions.

The information below is based on data from clinical studies involving over 8300 patients and extensive post-marketing experience.

The adverse reactions listed below are categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), unknown (frequency cannot be estimated from available data). Within each frequency grouping, adverse events are listed in order of decreasing occurrence.

Classes and Systems	Common	Uncommon	Rare	Frequency unknown (cannot be estimated from available data)
Infections and infestations		Fungal infections, including infections caused by Candida species. Resistance of pathogenic microorganisms
Blood and lymphatic system disorders		Leukopenia Eosinophilia	Thrombocytopenia Neutropenia	Impairment of bone marrow function, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.
Immune system disorders			Angioedema Hypersensitivity (see section "Special precautions")	Anaphylactic shock 1 Anaphylactoid shock 1 (see section "Special precautions")
Endocrine system disorders			Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Gastrointestinal and metabolic disorders		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus Hypoglycemic coma (see section "Special precautions")	Hypoglycemia (see section "Special precautions")
Psychiatric disorders*	Insomnia	Anxiety Confusion Nervousness	Psychotic reactions (including hallucinations, paranoia) Depression Agitation Abnormal dreams Nightmares Delirium	Psychotic disorders with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions"). Mania
Central nervous system disorders*	Headache Dizziness	Drowsiness Tremor Dysgeusia	Seizures (see sections "Contraindications" and "Special precautions") Paraesthesia Memory impairment	Peripheral sensory neuropathy (see section "Special precautions") Parosmia, including anosmia Dyskinesia Extrapyramidal disorders Ageusia Loss of consciousness Benign intracranial hypertension Myoclonus
Eye disorders*			Visual disturbances, such as blurred vision (see section "Special precautions")	Transient loss of vision (see section "Special precautions"), uveitis
Ear and labyrinth disorders*		Vertigo	Tinnitus	Hearing loss Disturbances of hearing
Cardiac disorders**			Tachycardia Palpitations	Ventricular tachycardia, which may lead to cardiac arrest Ventricular arrhythmia and torsades de pointes-type ventricular tachycardia (observed mainly in patients with risk factors for QT interval prolongation), QT interval prolongation observed on ECG (see sections "Special precautions" and "Overdose")
Vascular disorders	Apply only to intravenous formulations: Phlebitis		Arterial hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm, allergic pneumonitis
Gastrointestinal disorders	Diarrhea Vomiting Nausea	Abdominal pain Dyspepsia Flatulence Constipation		Hemorrhagic diarrhea, which rarely may be a sign of colitis, including pseudomembranous colitis (see section "Special precautions") Pancreatitis (see section "Special precautions")
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated blood bilirubin levels		Jaundice and severe hepatic injury, including cases of acute liver failure, primarily in patients with severe underlying diseases (see section "Special precautions"), Hepatitis
Skin and subcutaneous tissue disorders2		Rash Pruritus Urticaria Hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions") Localized drug rash	Toxic epidermal necrolysis Stevens-Johnson syndrome Exudative multiform erythema Photosensitivity reactions, increased sensitivity to sunlight and ultraviolet radiation (see section "Special precautions") Leukocytoclastic vasculitis Stomatitis Skin hyperpigmentation
Musculoskeletal and connective tissue disorders*		Arthralgia Myalgia	Tendon disorders (see sections "Contraindications" and "Special precautions"), including tendinitis (e.g., Achilles tendon) Muscle weakness, which may be relevant in patients with myasthenia (see section "Special precautions")	Rhabdomyolysis Tendon rupture (e.g., Achilles tendon) (see sections "Contraindications" and "Special precautions") Ligament rupture Muscle rupture Arthritis
Renal and urinary disorders		Elevated serum creatinine levels	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions*	Apply only to intravenous formulations: Infusion site reaction (pain, redness)	Asthenia	Increased body temperature	Pain (including back, chest, and extremity pain); as with other fluoroquinolones, attacks of porphyria may occur in patients with porphyria.

1. Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose of the drug.

2. Skin and mucous membrane reactions may sometimes occur even after administration of the first dose of the drug.

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various systems of the body and sensory organs, sometimes involving several simultaneously (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, difficulty walking, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, taste and smell) (see section "Special precautions").

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

Other adverse effects associated with the use of fluoroquinolones include:

• porphyria attacks in patients with known porphyria;
• anxiety, suicidal thoughts, panic attacks, neuralgia, and difficulty concentrating, which may be manifestations of prolonged and disabling adverse reactions caused by fluoroquinolones.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children. Unused medicinal product should be destroyed.

Incompatibility.

Levofloxacin must not be mixed with heparin or solutions having an alkaline reaction (e.g. sodium bicarbonate solution), or with other medicinal products except those specified in the section "Method of administration and dosage."

Mixing with other infusion solutions

Levofloxacin is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose monohydrate solution;
• 2.5% dextrose in Ringer's solution;
• multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes).

Packaging. 100 ml of the drug in containers. One container in a pouch, in a box.

Prescription status. Prescription only.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer's address and location of its operations.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, India.

Marketing authorization holder. AAR PHARMA FZ-LLC, United Arab Emirates.

Address of the marketing authorization holder and/or its representative.

Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates.