Levostad®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOSTAD® (LEVOSTAD®)

Composition:

Active substance: levofloxacin;

One film-coated tablet contains 250 mg or 500 mg of levofloxacin (in the form of levofloxacin hemihydrate);

Excipients: microcrystalline cellulose; powdered cellulose; pregelatinized starch; corn starch; crospovidone; povidone; hypromellose; sodium stearyl fumarate; polyethylene glycol; lactose monohydrate; titanium dioxide (E 171); iron oxide red (E 172); iron oxide yellow (E 172); iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: pink film-coated oval-shaped tablets with a score line on both sides.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA12.

Pharmacological Properties

Pharmacodynamics

Levofloxacin is a synthetic antibacterial agent belonging to the fluoroquinolone group and is the S(-) enantiomer of the racemic mixture of the drug ofloxacin. As a fluoroquinolone-class antibacterial agent, levofloxacin acts on the DNA gyrase/DNA topoisomerase IV complex.

The bactericidal effect is achieved through inhibition by levofloxacin of the bacterial enzyme DNA gyrase, which belongs to type II topoisomerases. This inhibition prevents bacterial DNA from transitioning from a relaxed to a supercoiled state, thereby preventing further division (reproduction) of bacterial cells.

The level of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC). The spectrum of activity of levofloxacin includes Gram-positive and Gram-negative bacteria, including non-fermenting bacteria.

Mechanism of resistance. Resistance to levofloxacin develops through a stepwise mutation process at the target site in both type II topoisomerases: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as reduced permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

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

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

EUCAST clinical MIC breakpoints for levofloxacin (version 10.0; 01.01.2020):

1 - uncomplicated urinary tract infections only;

2 - susceptibility can be determined based on susceptibility to ciprofloxacin.

The prevalence of resistance may vary geographically and over time for individual species, and it is advisable to obtain local information on microbial resistance, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the usefulness of the drug at least questionable for certain types of infections.

Typically susceptible species.

Aerobic gram-positive bacteria: Bacillus anthracis, methicillin-susceptible Staphylococcus aureus, Staphylococcus saprophyticus, Streptococci - group 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 resistance may be a problem.

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

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

Anaerobic bacteria: Bacteroides fragilis.

* There is a very high likelihood of cross-resistance of methicillin-resistant S. aureus to fluoroquinolones, including levofloxacin.

Naturally resistant strains.

Aerobic gram-positive bacteria: Enterococcus faecium.

Pharmacokinetics.

Absorption. Orally administered levofloxacin is rapidly and almost completely absorbed; peak plasma concentration occurs within 1–2 hours after administration. Absolute bioavailability is 99–100%. Food has minimal effect on levofloxacin absorption.

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

Penetration into tissues and body fluids.

Penetration into bronchial mucus and epithelial lining fluid. Maximum concentrations of levofloxacin in bronchial mucus and bronchoalveolar lavage fluid after administration of 500 mg are 8.2 mg/g and 10.8 mg/g, respectively, achieved within 1 hour after administration.

Penetration into lung tissue. Maximum concentration of levofloxacin in lung tissue after administration of 500 mg is approximately 11.3 mg/g, achieved within 4–6 hours after administration. Levofloxacin concentration in lung tissue significantly exceeds its plasma concentration.

Penetration into bladder content. Maximum concentration of levofloxacin in bladder content after administration of 500 mg once or twice daily for 3 days is approximately 4.0–6.7 mg/g, achieved within 2–4 hours after administration.

Penetration into cerebrospinal fluid. Penetrates poorly.

Penetration into prostate tissue. Mean concentrations of levofloxacin in prostate tissue after administration of 500 mg once daily for 3 days are 8.7 mg/g, 8.2 mg/g, and 2 mg/g, achieved at 2, 6, and 24 hours after administration, respectively.

Concentration in urine. Mean urinary concentrations of levofloxacin after administration of 150 mg, 300 mg, or 500 mg once daily are 44 mg/L, 91 mg/L, and 200 mg/L, respectively, achieved within 8–12 hours after administration.

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

Elimination. After oral 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). There is no significant difference in levofloxacin pharmacokinetics between intravenous and oral administration. Mean total clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min.

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

Special patient populations.

Patients with renal impairment. Levofloxacin pharmacokinetics depend on renal function. With reduced renal excretion and clearance, elimination half-life increases.

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

Elderly patients. The pharmacokinetics of levofloxacin do not differ in young and elderly patients, except for differences in clearance.

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

Clinical characteristics.

Indications.

Mild to moderate infections caused by microorganisms sensitive to levofloxacin:

• acute bacterial sinusitis;*
• exacerbations of chronic obstructive pulmonary disease, including bronchitis;*
• community-acquired pneumonia;*
• complicated skin and soft tissue infections;*
  • uncomplicated cystitis;*

(*For the above-mentioned infections, levofloxacin should be prescribed only when use of other antibacterial agents typically recommended for treatment of these infections is considered inappropriate.)

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

The medicinal product may be used to complete the course of therapy in patients who have shown improvement during initial intravenous treatment with levofloxacin.

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

Contraindications.

Levofloxacin must not be used:

• in patients with hypersensitivity to levofloxacin or to other quinolones or to any of the excipients;
• in patients with epilepsy;
• in patients with a history of tendon disorders related to prior fluoroquinolone administration;
• in children and adolescents under 18 years of age;
• during pregnancy;
• in breastfeeding women.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on levofloxacin.

Iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine. The absorption of levofloxacin is significantly reduced when administered concomitantly with iron salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal formulations of didanosine containing aluminium- or magnesium-based buffering agents). Concomitant administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. It is not recommended to administer medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal formulations of didanosine containing aluminium- or magnesium-based buffering agents), within 2 hours before or after administration of the drug (see section "Dosage and administration"). Calcium salts have minimal effect on the absorption of levofloxacin after oral administration.

Sucralfate. The bioavailability of levofloxacin tablets is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to administer sucralfate 2 hours after taking the drug (see section "Dosage and administration").

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs. No pharmacokinetic interactions between levofloxacin and theophylline have been observed in clinical studies. However, a marked reduction in the cerebral seizure threshold may occur when quinolones are administered concomitantly with theophylline, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold.

Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.

Probenecid and cimetidine. Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin.

Renal clearance of levofloxacin decreases by 24% in the presence of cimetidine and by 34% with probenecid. This is because both agents can block tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical significance. Caution should be exercised when administering levofloxacin concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information. The following medicinal products do not have any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly: calcium carbonate, digoxin, glyburide, ranitidine.

Effects of levofloxacin on other medicinal products.

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

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

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL. Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic agents) (see section "Special precautions for use" ("QT interval prolongation")).

Other significant 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 a CYP1A2 inhibitor.

Other interactions. Food intake. No clinically significant interaction with food has been observed; therefore, the drug may be taken independently of food intake.

Alcohol consumption is not recommended during treatment with levofloxacin.

Special precautions for use.

Levofloxacin should be avoided in patients who have experienced serious adverse reactions in the past with quinolones or fluoroquinolones (see section "Adverse reactions").

Treatment of these patients with levofloxacin should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

Resistance development risk.

Methicillin-resistant S. aureus (MRSA). Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections caused by MRSA, except in cases where susceptibility of the microorganism to levofloxacin has been confirmed (and usually recommended antibacterial agents for MRSA infections are considered inappropriate).

Escherichia coli resistant to levofloxacin may commonly cause urinary tract infections, which should be taken into account when prescribing levofloxacin to patients with urinary tract diseases. Prescribers are advised to consider local prevalence of E. coli resistance to fluoroquinolones.

Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbations of chronic bronchitis if these infections have been properly diagnosed.

Inhalational anthrax. Clinical experience is based on in vitro susceptibility studies of Bacillus anthracis, as well as experimental animal data together with limited human data. Physicians should follow nationally and/or internationally agreed guidelines for the treatment of anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions. Very rarely, patients receiving quinolones and fluoroquinolones, regardless of age and presence of risk factors, have experienced prolonged (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems (including musculoskeletal, nervous, psychiatric and sensory systems). The medicinal product should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Tendinitis and tendon rupture. Tendinitis, which may lead to tendon rupture including Achilles tendon, may occur during treatment with quinolones. Tendinitis and tendon ruptures, sometimes bilateral, may occur within 48 hours after administration of levofloxacin and even several months after discontinuation of levofloxacin. Patients most susceptible to tendinitis and tendon ruptures are those aged 60 years and older, patients receiving a daily dose of 1000 mg levofloxacin, and those receiving concomitant corticosteroid therapy.

Therefore, elderly patients should be carefully monitored when prescribed levofloxacin.

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

Clostridium difficile-associated disease. Diarrhea, especially severe, persistent and/or hemorrhagic, during or after treatment with the drug may be a symptom of disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, the drug should be discontinued immediately, and patients should be urgently treated with supportive measures; specific therapy may also be required (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.

Patients with predisposition to seizures. The drug is contraindicated in patients with a history of epilepsy. As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures, particularly those with central nervous system disorders, concomitant therapy with fenbufen or similar non-steroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, treatment with levofloxacin must be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency. Patients with latent or existing defects in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in these patients.

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

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

Severe skin reactions. Severe skin reactions such as toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with levofloxacin use. Patients should be warned about signs and symptoms of these severe skin reactions when the medicinal product is prescribed, and close monitoring should be established. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Reinitiation of levofloxacin treatment in patients who have developed such serious reactions as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during levofloxacin use is prohibited.

Blood glucose alterations. As with other quinolones, alterations in blood glucose levels, including both hyperglycemia and hypoglycemia, may occur, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, monitoring of blood glucose levels is recommended. Treatment with the drug should be discontinued immediately if the patient reports disturbances in blood glucose levels, and alternative antibiotic therapy from a non-fluoroquinolone class should be considered.

Phototoxicity prevention. Although phototoxicity occurs very rarely with levofloxacin, patients are advised not to expose themselves to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) unnecessarily during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists. Since increased coagulation test results (INR/PT) and/or bleeding may occur in patients taking levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation test parameters should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions. Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. Very rarely, these led to suicidal thoughts and self-destructive behavior, sometimes even after a single dose of levofloxacin (see section "Adverse reactions"). If these reactions occur, levofloxacin should be discontinued immediately at the first signs or symptoms, and patients should be advised to seek medical advice. Alternative antibiotic therapy from a non-fluoroquinolone class should be considered, and appropriate measures taken. Caution should be exercised if levofloxacin must be used in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation. Fluoroquinolones, including levofloxacin, should be used with caution in patients with 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);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• advanced age;
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women are 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").

Peripheral neuropathy. Sensory and sensorimotor peripheral neuropathy, which may occur suddenly, has been reported in patients taking fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, to prevent the development of irreversible conditions.

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

Myasthenia. 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 in patients with myasthenia gravis during post-marketing use of 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, immediate consultation with an ophthalmologist is required.

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 test results. Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological testing of patients with tuberculosis.

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

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

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

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

• risk factors for both aortic aneurysm and dissection and cardiac valve 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
• risk factors for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or
• risk factors for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).

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

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

Patients should be recommended to seek immediate medical help if acute dyspnea, new palpitations, or development of abdominal swelling or lower limb edema occur.

Acute pancreatitis. Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting require immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued; if acute pancreatitis is confirmed, levofloxacin should not be restarted. Caution should be exercised when treating patients with a history of pancreatitis.

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

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., it can be considered essentially "sodium-free".

Use during pregnancy or breastfeeding. Due to the lack of studies and the potential for quinolones to damage joint cartilage in the growing organism, Levostad® is contraindicated in pregnant and breastfeeding women. If pregnancy is diagnosed during treatment with the drug, this should be reported to the physician.

Levofloxacin did not cause impairment of fertility or reproductive function in animals.

Ability to affect reaction speed when driving vehicles or operating machinery. Levofloxacin has a minor or moderate influence on the ability to drive vehicles or operate machinery.

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

Method of administration and dosage

The drug should be taken 1 or 2 times daily. The dosage depends on the type and severity of the infection. The duration of treatment depends on the course of the disease. It is recommended to continue treatment with the drug for at least 48–72 hours after normalization of body temperature or until microbiological tests have confirmed eradication of the causative organism.

Levostad may also be used to complete the course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment; due to the bioequivalence of parenteral and oral formulations, the same dosage may be used.

Dosage for adult patients with normal renal function, in whom creatinine clearance is over 50 mL/min

Dosage for patients with renal impairment with creatinine clearance less than or equal to 50 ml/min

1 – No additional doses are required after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).

* Administer at the appropriate dosage.

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

Dosing in elderly patients. If renal function is not impaired, dose adjustment is not necessary, except for adjustments based on renal function (see section "Tendinitis and tendon rupture" and "QT interval prolongation").

Method of administration. Tablets should be swallowed whole with sufficient fluid. They may be divided along the break line for dose adjustment. Tablets may be taken during or between meals. Tablets should be taken at least two hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only didanosine formulations containing aluminum or magnesium buffering agents), and sucralfate, as absorption of the drug may be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Children

The use of the drug is contraindicated in children under 18 years of age, due to the potential risk of damage to joint cartilage.

Overdose

Based on results from animal toxicity studies or clinical pharmacology studies using supratherapeutic doses, the most significant signs expected after acute levofloxacin overdose include central nervous system (CNS) symptoms such as confusion, dizziness, altered consciousness, and seizures, as well as QT interval prolongation and gastrointestinal reactions such as mucosal erosions.

In post-marketing experience, CNS effects observed in such cases have included confusion, seizures, myoclonus, hallucinations, and tremor.

In case of overdose, symptomatic treatment should be administered. Due to the potential for QT interval prolongation, ECG monitoring is required. Antacids may be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis and chronic ambulatory peritoneal dialysis, is not effective in removing levofloxacin from the body. There is no specific antidote for this drug.

Adverse Reactions

Frequency categories were defined according to the following criteria: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

Within each frequency group, adverse reactions are listed in decreasing order of severity.

a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

b Skin and mucous membrane reactions may sometimes occur even after the first dose.

Other adverse reactions associated with the use of fluoroquinolones:

Ÿ Acute attacks of porphyria in patients with porphyria.

* In very rare cases, in patients receiving quinolones and fluoroquinolones, sometimes regardless of the presence of risk factors, prolonged (for several months or years), disabling and potentially irreversible serious adverse reactions have been observed, affecting various body systems and sensory organs (such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, suicidal thoughts, memory and concentration impairment), hearing, vision, taste and smell disturbances) (see section "Special precautions for use").

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

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

5 tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

STADA Arzneimittel AG, Germany.

Manufacturer's address and location of its business operations.

Stadastrasse 2-18, 61118 Bad Vilbel, Germany.