Abiflox®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABYFLOX® (ABYFLOX®)

Composition:

Active substance: levofloxacin;

100 ml of solution contains levofloxacin hemihydrate equivalent to levofloxacin 500 mg;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear solution ranging in color from pale yellow to greenish-yellow.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin.

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.

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

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC).

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.

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

Table 1

EUCAST clinical breakpoints for levofloxacin (20.06.2006)

Pathogen	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. pneumoniae1	≤ 2 mg/L	> 2 mg/L
Streptococcus A, B, C, G	≤ 1 mg/L	> 2 mg/L
H. influenzae M. catarrhalis2	≤ 1 mg/L	> 1 mg/L
Non-species-related breakpoints3	≤ 1 mg/L	> 2 mg/L
1 The MIC breakpoint between susceptible and intermediate (moderately resistant) strains has been increased from 1 to 2 mg/L to suppress the growth of wild-type strains of this microorganism showing variability in this parameter. Breakpoints apply to high-dose therapy. 2 Strains with MIC values above the breakpoint between susceptible and intermediate (moderately resistant) strains are very rare or have not yet been reported. Testing for identification and antimicrobial susceptibility of any such isolate should be repeated, and if confirmed, the isolate should be sent to a reference laboratory. 3 Non-species-related MIC breakpoints were defined primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the MIC distribution of specific species. Non-species-related MIC breakpoints are intended for use only with species for which no species-specific breakpoint has been defined, and are not used for species where susceptibility testing is not recommended or for which there is insufficient evidence (e.g., Enterococcus, Neisseria, gram-negative anaerobes).

The recommended CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) MIC breakpoints for levofloxacin, which distinguish susceptible from intermediate organisms and intermediate from resistant organisms, are provided in Table 2 for MIC testing (µg/mL) or disk diffusion method (zone diameter [mm] using a 5 µg levofloxacin disk).

Table 2

Recommended CLSI MIC and disk diffusion breakpoints for levofloxacin (M100-S17, 2007)

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Non-Enterobacteriaceae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Acinetobacter spp.	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Stenotrophomonas maltophilia	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Staphylococcus spp.	≤ 1 µg/mL ≥19 mm	≥ 4 µg/mL ≤ 15 mm
Enterococcus spp.	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
H. influenzae M. catarrhalis1	≤ 2 µg/mL ≥17 mm
Streptococcus pneumoniae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Beta-hemolytic Streptococcus	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
1 The absence or rare occurrence of resistant strains precludes the definition of any other result categories except “susceptible.” For isolates yielding results indicating the “resistant” category, organism identification and antimicrobial susceptibility test results should be confirmed in a reference laboratory using the CLSI reference dilution method.

Antibacterial spectrum

The prevalence of resistance in selected species may vary geographically and over time. Local information on resistance patterns is desirable, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the agent at least questionable for certain types of infections.

Susceptible organisms

Gram-positive aerobic bacteria

Staphylococcus aureus * (methicillin-susceptible), Staphylococcus saprophyticus, Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae *, Streptococcus pyogenes *.

Gram-negative aerobic bacteria

Burkholderia cepacia **, Eikenella corrodens, Haemophilus influenzae *, Haemophilus parainfluenzae *, Klebsiella oxytoca, Klebsiella pneumoniae *, Moraxella catarrhalis *, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria

Peptostreptococcus.

Other organisms

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

Organisms for which acquired (secondary) resistance may be problematic.

Gram-positive aerobic bacteria

Enterococcus faecalis *, Staphylococcus aureus (methicillin-resistant), Staphylococcus coagulase spp.

Gram-negative aerobic bacteria

Acinetobacter baumannii *, Citrobacter freundii *, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae *, Escherichia coli *, Morganella morganii *, Proteus mirabilis *, Providencia stuartii, Pseudomonas aeruginosa *, Serratia marcescens *.

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus **, Bacteroides thetaiotaomicron **, Bacteroides vulgatus **, Clostridium difficile **.

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

** Naturally intermediate susceptibility.

Other data

Hospital-acquired infections caused by P. aeruginosa may require combination therapy.

Pharmacokinetics

Absorption

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.

After intravenous administration, levofloxacin accumulates in bronchial mucosa, lung tissue, bronchial secretions, and urine. Penetration into cerebrospinal fluid is low.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. There is virtually no accumulation effect with repeated administration of 500 mg once daily. A slight but predictable accumulation occurs with 500 mg twice daily. Steady-state levels are achieved within 3 days.

Penetration into tissues and body fluids

Penetration into bronchial mucosa and bronchial secretions of lung tissue (BSLT)

Maximum concentrations of levofloxacin in bronchial mucosa and bronchial secretions after a 500 mg oral dose were 8.3 µg/g and 10.8 µg/mL, respectively, reached within 1 hour after dosing.

Penetration into lung tissue

Maximum concentration of levofloxacin in lung tissue after a 500 mg oral dose was approximately 11.3 µg/g, achieved 4–6 hours after administration. Concentrations in lung tissue exceed those in plasma.

Penetration into bladder contents

Maximum concentration of levofloxacin in bladder contents of 4–6.7 µg/mL was achieved 2–4 hours after dosing over 3 days of treatment with 500 mg once or twice daily, respectively.

Penetration into cerebrospinal (spinal) fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue

After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue were 8.7 µg/g, 8.2 µg/g, and 2 µg/g at 2, 6, and 24 hours, respectively. The mean prostate/plasma concentration ratio was 1.84.

Urine concentration

Mean urine concentrations 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg levofloxacin were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Biotransformation

Levofloxacin undergoes minimal metabolism, forming desmethyl-levofloxacin and levofloxacin N-oxide as metabolites. These metabolites account for less than 5% of the total drug 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). Renal excretion is the primary route of elimination (over 85% of the administered dose).

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 exhibits linear pharmacokinetics in the range of 50–600 mg.

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 Table 3.

Table 3

Creatinine clearance (mL/min)	< 20	20–40	50–80
Renal clearance (mL/min)	13	26	57
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 in male and female patients demonstrated minor differences in levofloxacin pharmacokinetics depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

Levofloxacin, infusion solution is indicated for the treatment of the following infections in adults:

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

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

• Acute pyelonephritis and complicated urinary tract infections;
• Chronic bacterial prostatitis;
• Pulmonary form of anthrax: post-exposure prophylaxis and treatment.

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

Contraindications.

Levofloxacin should not be prescribed in the following cases:

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

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on Abiflox®

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. The concentration of levofloxacin was 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 the study, it is unlikely that statistically significant kinetic differences would be clinically relevant. Levofloxacin should be used with caution in combination with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

Calcium carbonate, digoxin, glyburide, and ranitidine do not show any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly.

Effect of Abiflox® on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (INR/international normalized ratio) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concomitantly (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 known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, and macrolides) (see section "Special precautions for use" (QT interval prolongation)).

Other relevant information

No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.

Special precautions for use

Patients with a history of serious adverse reactions to quinolone or fluoroquinolone drugs (see section "Adverse reactions") should avoid the use of levofloxacin. Treatment with levofloxacin in such patients should only be considered after careful benefit-risk assessment and in the absence of alternative treatment options (see section "Contraindications").

The benefit of treatment with levofloxacin, especially in cases of mild infections, should be carefully weighed according to the information provided in the section "Special precautions for use".

Prolonged, disabling and potentially irreversible serious adverse reactions

Very rare cases of prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous system, psychiatric, sensory organs) have been observed in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin administration should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and patients should be advised to seek medical attention.

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 the 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 causative agent of urinary tract infections, to fluoroquinolones varies across different countries of the European Union. Physicians should take into account the local prevalence of E. coli resistance to fluoroquinolones when prescribing levofloxacin.

Aortic aneurysm and aortic dissection

Epidemiological data suggest an increased risk of aortic aneurysm or aortic dissection with fluoroquinolone use, particularly in elderly patients. Therefore, fluoroquinolone antibiotics should be used only after careful benefit-risk assessment and consideration of alternative treatment options in patients with aortic aneurysm/dissection, patients with a family history of aortic aneurysm, and patients with risk factors or conditions predisposing to aortic aneurysm/dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, and atherosclerosis).

In case of sudden abdominal, chest or back pain, patients should seek immediate emergency medical assistance.

Duration of infusion

The recommended duration of infusion is at least 60 minutes for the 500 mg infusion solution. With ofloxacin, tachycardia and transient increase in blood pressure have been observed during infusion. In rare cases, sudden drop in blood pressure and circulatory collapse may occur as a consequence. If a marked decrease in blood pressure occurs during levofloxacin (l-isomer of ofloxacin) infusion, the infusion should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis may rarely occur, most commonly affecting the Achilles tendon and potentially leading to tendon rupture. Tendinitis and tendon ruptures, sometimes bilateral, may occur within 48 hours after starting levofloxacin or even several months after discontinuation. Patients at greatest risk include those aged 60 years or older, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving corticosteroid therapy. Patients who have undergone organ transplantation are at 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 closely monitored. Patients should consult their physician if they experience symptoms suggestive of tendinitis. If tendinitis is suspected, treatment should be discontinued immediately and appropriate management initiated (e.g., immobilization of the affected tendon).

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent and/or hemorrhagic, occurring during or after treatment (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 levofloxacin therapy. If pseudomembranous colitis is suspected, the infusion should be stopped immediately and appropriate treatment initiated without delay. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. The drug is contraindicated in patients with a history of epilepsy. The drug (like other quinolones) should be used with extreme caution in patients predisposed to seizures, particularly those with prior central nervous system (CNS) 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, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or known glucose-6-phosphate dehydrogenase deficiency are at risk of hemolytic reactions during treatment with quinolone antibiotics; 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 eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency).

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 discontinue treatment immediately and seek medical attention.

Dysglycemia

As with other 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., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients.

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 treatment and for 48 hours after discontinuation of levofloxacin to minimize the risk.

Patients receiving vitamin K antagonists

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

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, these progressed to suicidal thoughts and self-harming behavior, sometimes after only one dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with a history of psychotic disorders or psychiatric illness.

QT interval prolongation

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

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

Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", "Elderly patients", "Overdose", "Adverse reactions").

Peripheral neuropathy

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

Hepatobiliary disorders

Cases of necrotizing hepatitis up to life-threatening hepatic 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 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, 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 post-marketing 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 seek immediate consultation with an ophthalmologist (see sections "Ability to affect reaction speed when driving or operating machinery", "Adverse reactions").

Superinfection

Use of levofloxacin, especially over prolonged periods, 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, which may lead to false-negative results in bacteriological testing of patients with tuberculosis.

Sodium

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

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolone-induced damage to the developing joint cartilage, levofloxacin is contraindicated in pregnant women and women who are breastfeeding. If a patient becomes pregnant during treatment, she should inform her physician.

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

Fertility. Levofloxacin did not cause disorders of fertility or reproductive function in animal studies.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Prior to administration, a sensitivity test should be performed. The medicinal product should be administered slowly intravenously 1–2 times daily by drip infusion. The dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the medicinal product. Treatment with levofloxacin may be initiated intravenously and continued orally, provided such a switch is appropriate for the individual patient. Due to the bioequivalence of parenteral and oral dosage forms, the same dose may be used.

As with other antibacterial agents, it is recommended to continue treatment for at least 48–72 hours after normalization of body temperature or until microbiological tests have confirmed eradication of the causative pathogens.

Table 4

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

Indications	Daily dosage regimen* (based on patient's body weight)
Community-acquired pneumonia	500 mg once or twice daily, 7–14 days
Complicated urinary tract infections	500 mg once daily, 7–14 days
Acute pyelonephritis	500 mg once daily, 7–10 days
Chronic bacterial prostatitis	500 mg once daily, 28 days
Skin and soft tissue infections	500 mg once or twice daily, 7–14 days
Pulmonary form of anthrax	500 mg once daily, 8 weeks

* According to the patient's clinical condition, a switch from initial intravenous to oral administration at the same dosage may be possible after a few days (usually within 2–4 days).

Since levofloxacin is primarily eliminated via the kidneys, the dose should be reduced in patients with impaired renal function.

Table 5

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

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

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

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

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

The drug is administered intravenously by slow infusion. The duration of infusion of the contents of one vial (100 mL of solution for intravenous infusion containing 500 mg of levofloxacin) should be at least 60 minutes. The drug should be used immediately after puncturing the rubber stopper (within 3 hours) to prevent any bacterial contamination. Protection from light during infusion is not required.

Storage period after first opening – 3 days.

The diluted solution should be stored for up to 3 hours at a temperature not exceeding 25 °C.

Children.

The use of the drug is contraindicated in children (under 18 years of age), as damage to articular cartilage cannot be excluded.

Overdose.

Symptoms: dizziness, disturbance/confusion of consciousness, convulsive seizures, tremor, QT interval prolongation.

Treatment: in case of overdose, close monitoring of the patient, including ECG, is required. Treatment is symptomatic. Hemodialysis, including peritoneal dialysis or CAPD, is not effective for removing levofloxacin from the body. There are no specific antidotes.

Adverse Reactions.

Infections and infestations: fungal infections, including Candida species, resistance of pathogenic microorganisms.

Blood and lymphatic system disorders: leucopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, pancytopenia, haemolytic anaemia.

Immune system disorders: anaphylactic shock (see section "Special warnings and precautions for use"), hypersensitivity (see section "Special warnings and precautions for use"). Anaphylactic and anaphylactoid reactions may occasionally occur even after the first dose.

Metabolism and nutrition disorders: anorexia, hypoglycaemia, particularly in patients with diabetes (see section "Special warnings and precautions for use").

Psychiatric disorders*: insomnia, restlessness, psychotic reactions (including hallucinations, paranoia), depression, confusion, anxiety, agitation, nervousness, unusual dreams, nightmares, psychotic reactions with self-destructive behaviour, including suicidal ideation or actions (see section "Special warnings and precautions for use").

Nervous system disorders*: dizziness, headache, somnolence, convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), tremor, paraesthesia, sensory or sensorimotor peripheral neuropathy (see section "Special warnings and precautions for use"), dysgeusia (subjective taste disturbance), including ageusia (loss of taste), parosmia (disturbance of smell), including anosmia (loss of smell), dyskinesia (disturbance of motor coordination), extrapyramidal disorders, syncope (fainting), benign intracranial hypertension.

Eye disorders*: visual disturbances such as blurred vision or temporary loss of vision (see section "Special warnings and precautions for use"), uveitis.

Ear and labyrinth disorders*: vertigo, hearing impairment, tinnitus, hearing loss.

Cardiac disorders: tachycardia, palpitations, ventricular tachycardia which may lead to cardiac arrest, ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG (see sections "Special warnings and precautions for use" and "Overdose").

Vascular disorders: phlebitis, arterial hypotension.

Respiratory system disorders: bronchospasm, dyspnoea, allergic pneumonitis.

Gastrointestinal disorders: diarrhoea, nausea, vomiting, abdominal pain, dyspepsia, bloating, constipation, haemorrhagic diarrhoea, which in rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis.

Hepatobiliary disorders: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); increased blood bilirubin; hepatitis; jaundice and severe liver damage, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, hyperhidrosis, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*: arthralgia, myalgia, tendon disorders (see section "Special warnings and precautions for use"), including tendinitis (e.g., Achilles tendon); tendon rupture (see section "Special warnings and precautions for use"). Muscle weakness may occur, which may be particularly significant in patients with myasthenia gravis; muscle disorders (rhabdomyolysis).

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

General disorders and administration site conditions*: infusion site reactions (pain, redness), asthenia, pyrexia, pain (including back, chest and limb pain).

Other adverse effects associated with fluoroquinolone use: extrapyramidal symptoms and other disturbances of motor coordination, hypersensitivity vasculitis, porphyria attacks in patients with known porphyria.

*With the use of quinolones and fluoroquinolones, very rare cases of prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions have been reported, sometimes affecting multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste and smell), in some cases occurring independently of risk factors (see section "Special warnings and precautions for use").

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Incompatibilities.

Levofloxacin must not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate) or with other medicinal products whose compatibility has not been established.

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 solution in a vial; 1 vial in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

DEMO S.A. Pharmaceutical Industry.

Manufacturer's address and place of business.

21st km Athens-Lamia National Road, Kryoneri Attica, 14568, Greece.