Tigeron film-coated tablets 500 mg blister No. 10

Instructions Tigeron film-coated tablets 500 mg blister No. 10

Composition

active ingredient: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin 500 mg or

750 mg;

excipients: povidone K29/32, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry 03B84681 pink coating: hypromellose, titanium dioxide (E 171), polyethylene glycols, red iron oxide (E 172), yellow iron oxide (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated, pink tablets with embossing "500" or "750" on one side.

Pharmacotherapeutic group

Antibacterials of the quinolone group. Fluoroquinolones. ATX code J01M A12.

Pharmacological properties

Pharmacodynamics

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

Mechanism of action.

As an antibacterial agent from the fluoroquinolone group, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetics/pharmacodynamics relationship.

The degree of bactericidal activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic curve (AUC) and the minimum inhibitory concentration (MIC).

Mechanism of resistance.

Resistance to levofloxacin is acquired by a stepwise process of target site mutation in both types of topoisomerase II, DNA gyrase, and topoisomerase IV. Other resistance mechanisms, such as barrier penetration (common in Pseudomonas aeruginosa) and efflux mechanisms, may also influence levofloxacin susceptibility.

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 drugs is generally not expected.

Checkpoints.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended MIC breakpoints for levofloxacin that distinguish susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the MIC test table below (mg/L).

EUCAST Clinical MIC Breakpoints for Levofloxacin (Version 2.0, 2012-01-01)

The prevalence of resistance may vary geographically and over time for individual species. It is advisable to obtain local information on the resistance patterns of microorganisms, particularly when treating severe infections. As necessary, specialist advice should be sought when the local prevalence of resistance is such that the benefit of the agent, at least in some types of infections, is questionable.

*Methicillin-resistant S. aureus is likely to have cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics

Absorption.

Orally administered levofloxacin is rapidly and almost completely absorbed, with Cmax achieved in 1-2 hours. Absolute bioavailability is 99-100%.

Food has little effect on the absorption of levofloxacin.

Steady state is achieved within 48 hours with a dosage regimen of 500 mg 1 or 2 times a day.

Distribution.

Approximately 30-40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated doses of 500 mg, indicating extensive distribution into body tissues.

Penetration into body tissues and fluids.

Levofloxacin has been shown to penetrate bronchial mucosa, bronchial secretions of lung tissue, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin is metabolized to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites constitute

Breeding.

After oral and intravenous administration, levofloxacin is eliminated from the blood plasma relatively slowly (half-life (t1/2) is 6-8 hours). It is excreted mainly by the kidneys (>85% of the administered dose). The mean total clearance of levofloxacin after a single dose of 500 mg was 175 ± 29.2 ml/min. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating the interchangeability of these routes of administration.

Linearity.

Levofloxacin has linear pharmacokinetics in the range of 50 to 1000 mg.

Patients with renal failure.

The pharmacokinetics of levofloxacin are affected by the degree of renal impairment. As renal function deteriorates, renal excretion and clearance decrease and t1/2 increases as shown in the table below.

Pharmacokinetics in renal failure after a single oral dose of 500 mg:

Elderly patients.

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

Gender differences.

Separate analyses of male and female patients demonstrated slight gender differences in the pharmacokinetics of levofloxacin. There is no evidence that these gender differences are clinically relevant.

Indication

The drug is prescribed to adults for the treatment of the following infections:

• Acute bacterial sinusitis.

• Exacerbation of chronic obstructive pulmonary disease, including bronchitis.

• Community-acquired pneumonia.

• Complicated skin and soft tissue infections.

• Uncomplicated cystitis.

In the above infections, the drug should be used only when it is considered inappropriate to use antibacterial drugs that are usually recommended for the initial treatment of these infections.

• Acute pyelonephritis and complicated urinary tract infections.

• Chronic bacterial prostatitis.

The drug can also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin.

Official recommendations on the appropriate use of antibacterial drugs should be considered.

Contraindication

Hypersensitivity to levofloxacin, other quinolones or to the excipients of the drug.

Epilepsy.

History of tendon lesions due to fluoroquinolone use.

Childhood.

Pregnancy and breastfeeding.

Interaction with other medicinal products and other types of interactions

Effects of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium and aluminum, didanosine.

Levofloxacin absorption is significantly reduced when taken simultaneously with iron salts or antacids containing magnesium or aluminum, or didanosine (only for forms containing aluminum or magnesium buffering agents). Concomitant use of fluoroquinolones with multivitamins containing zinc leads to a decrease in their oral absorption. It is not recommended to take drugs containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for forms of didanosine containing aluminum or magnesium buffering agents), within 2 hours before/after levofloxacin administration. Calcium salts had minimal effect on the oral absorption of levofloxacin.

Sucralfate.

The bioavailability of levofloxacin is significantly reduced when co-administered with sucralfate. If a patient needs to receive both sucralfate and levofloxacin, it is best to take sucralfate 2 hours after taking levofloxacin.

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

Probenecid and cimetidine.

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin is reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are able to block the tubular secretion of levofloxacin. However, statistically significant kinetic differences are unlikely to be of clinical relevance. Levofloxacin should be administered with caution when drugs that affect tubular secretion, such as probenecid and cimetidine, are administered concomitantly, especially in patients with renal impairment.

Other significant information.

It is known that no clinically significant effect was caused on the pharmacokinetics of levofloxacin when used together with calcium carbonate, digoxin, glibenclamide, ranitidine.

Effect of levofloxacin on other drugs

Cyclosporine.

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

Vitamin K antagonists.

Increased coagulation tests (PC/MC) and/or bleeding, which may be severe, have been reported with concomitant use of vitamin K antagonists (e.g. warfarin). Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists.

Drugs that prolong the QT interval.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics).

Other relevant information: Levofloxacin did not affect the pharmacokinetics of theophylline (which is a marker substrate for the CYP1A2 enzyme), indicating that levofloxacin is not a CYP1A2 inhibitor.

Other types of interaction

Food.

No clinically significant interaction with food was observed. Thus, the drug can be taken regardless of food intake.

Application features

Levofloxacin should be avoided in patients with a history of serious adverse reactions to quinolone or fluoroquinolone-containing medicinal products (see section 4.8). Levofloxacin should only be initiated in such patients if no alternative treatment options are available and after a careful benefit/risk assessment (see also section 4.8).

Prolonged, disabling and potentially irreversible serious adverse reactions

Very rare, prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various, or sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and sensory) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age or existing risk factors. At the first signs or symptoms of any serious adverse reaction, levofloxacin should be discontinued immediately and a doctor should be consulted.

Methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) has a very high potential for cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA unless laboratory testing has confirmed that the pathogen is susceptible to levofloxacin.

Levofloxacin can be used to treat acute bacterial sinusitis and exacerbation of chronic bronchitis, if these infections have been appropriately diagnosed.

Fluoroquinolone resistance in Escherichia coli (the most common cause of urinary tract infections) varies between countries. The local prevalence of fluoroquinolone resistance in Escherichia coli should be taken into account when prescribing fluoroquinolones.

Tendinitis and tendon ruptures.

Tendinitis and tendon ruptures (especially of the Achilles tendon, but not limited to it), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones or even several months after stopping therapy. Elderly patients, or patients with impaired renal function or organ transplant recipients, and those taking corticosteroids are at higher risk of developing tendinitis and tendon ruptures. Therefore, concomitant use of corticosteroids with levofloxacin should be avoided.

At the first signs of tendinitis (e.g. inflammation and swelling accompanied by pain), levofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be treated appropriately (e.g. immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Diarrhoea, particularly severe, persistent and/or haemorrhagic, during or after treatment with the drug (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD can range in severity from mild to life-threatening; the most severe form is pseudomembranous colitis. It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, the drug should be discontinued immediately and appropriate therapy should be initiated without delay. Antiperistaltic medicinal products are contraindicated in this clinical situation.

Patients prone to seizures.

Quinolones may lower the seizure threshold and cause seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications") and, as with other quinolones, should be used with extreme caution in patients prone to seizures or in concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). In the event of seizures, levofloxacin treatment should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or present defects in glucose-6-phosphate dehydrogenase activity may be predisposed to hemolytic reactions when treated with quinolone antibacterial agents. Therefore, if levofloxacin is to be used in these patients, the possible occurrence of hemolysis should be monitored.

Patients with renal failure.

Since levofloxacin is excreted primarily by the kidneys, the dose of the drug must be adjusted for patients with impaired renal function.

Hypersensitivity reactions.

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), sometimes after the first dose. In such cases, patients should immediately discontinue treatment and consult a doctor or call an ambulance for appropriate emergency measures.

Severe skin adverse reactions

Severe skin reactions, which may be life-threatening or fatal, have been reported with levofloxacin, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug rash with eosinophilia and systemic symptoms (DRESS). Patients should be advised of the signs and symptoms of severe skin reactions and monitored closely when prescribing the drug. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment should be considered. If a patient develops one of the serious adverse reactions, such as TSE, TEN, or DRESS, levofloxacin should not be restarted under any circumstances.

Change in blood glucose levels.

Changes in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with the use of quinolones, especially in diabetic patients receiving concomitant oral hypoglycemic agents (e.g. glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in diabetic patients (see section 4.8). If a patient reports abnormalities in blood glucose levels, levofloxacin treatment should be discontinued immediately and alternative antibacterial therapy should be considered.

Prevention of photosensitization.

Photosensitivity has been reported with levofloxacin. To prevent photosensitivity, patients are advised to avoid exposure to strong sunlight or artificial sources of UV light (e.g., artificial ultraviolet lamps, tanning beds) during treatment and for 48 hours after stopping levofloxacin.

Patients receiving vitamin K antagonists.

Due to the possible increase in coagulation tests (PC/MC) and/or bleeding in patients taking levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored if these drugs are used concomitantly.

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these have progressed to suicidal ideation and self-harm, sometimes after only a single dose of levofloxacin. If a patient experiences these reactions, levofloxacin should be discontinued and appropriate measures should be taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT prolongation.

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

- congenital long QT syndrome;

- uncorrected electrolyte imbalance (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, so caution should be exercised when administering fluoroquinolones, including levofloxacin, to these patient groups.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paresthesia, hypoesthesia, dysesthesia or weakness have been reported in patients treated with quinolones or fluoroquinolones. Patients taking levofloxacin are advised to report to their physician the development of the following symptoms of neuropathy: pain, burning, tingling, numbness or weakness, before continuing treatment, in order to prevent the development of a potentially irreversible condition (see section "Adverse reactions").

Genitobiliary disorders.

Cases of necrotizing hepatitis and fatal hepatic failure have been reported with levofloxacin, predominantly in patients with severe underlying medical conditions such as sepsis. Patients should be advised to discontinue treatment and seek medical attention if signs and symptoms of liver disease such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may cause muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported in the post-marketing setting with fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual impairment.

If any visual disturbances occur while taking levofloxacin, you should immediately consult an ophthalmologist.

Superinfection.

The use of levofloxacin, especially long-term, may lead to the growth of resistant microorganisms. If superinfection develops during therapy, appropriate measures should be taken.

Impact on laboratory test results.

In patients treated with levofloxacin, urine opiates may give false-positive results. It may be necessary to confirm positive opiates with more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and therefore lead to false-negative results in bacteriological diagnosis of tuberculosis.

Aortic aneurysm/dissection, regurgitation/heart valve insufficiency.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, especially in elderly patients, and aortic and mitral valve regurgitation after the use of fluoroquinolones.

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of other treatment options in patients with a history of aortic aneurysm or congenital heart valve disease, or in patients with aortic aneurysm and/or dissection or heart valve disease and other risk factors or conditions predisposing to their development:

- both for aortic aneurysm/dissection and for heart valve regurgitation/insufficiency (e.g. connective tissue diseases such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis);

- for aortic aneurysm/dissection (e.g. vascular diseases such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome);

- for regurgitation/heart valve insufficiency (e.g. infective endocarditis).

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

Patients should seek emergency medical attention immediately if they experience severe abdominal, chest, or back pain.

Patients should be advised to seek immediate medical attention if they experience acute shortness of breath, new onset of palpitations, or swelling of the abdomen or lower extremities.

Use during pregnancy or breastfeeding

Pregnancy.

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

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. However, in the absence of human studies and based on experimental data indicating a risk of damage to the articular cartilage of the growing organism by fluoroquinolones, levofloxacin should not be administered to pregnant women.

Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the excretion 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 the articular cartilage of the growing fetus, levofloxacin should not be administered to women who are breastfeeding.

Fertility.

Levofloxacin is known not to cause impairment of fertility and reproductive function in rats.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some adverse reactions (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient's ability to concentrate and react quickly and thus pose an increased risk in situations where these qualities are of particular importance (e.g. driving a car or operating machinery).

Method of administration and doses

The drug should be taken 1 or 2 times a day. The dose depends on the type, severity of the infection and the sensitivity of the probable pathogen.

The drug can also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin; given the bioequivalence of parenteral and oral forms, the same dosage can be used.

Dosage. The following dosage recommendations can be given for the drug:

Dosage for patients with normal renal function (creatinine clearance > 50 mL/min)

*Since the tablet is not divisible, if the drug is prescribed in a dose of 250 mg or less, levofloxacin preparations with the possibility of such a dosage should be used.

Special populations

Dosage for patients with renal impairment (creatinine clearance ≤50 mL/min)

*Since the tablet is not divisible, if the drug is prescribed in a dose of 250 mg or less, levofloxacin preparations with the possibility of such a dosage should be used.

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

Hepatic impairment: No dose adjustment is required since levofloxacin is only slightly metabolized in the liver and is excreted primarily by the kidneys.

Elderly patients: If renal function is not impaired, no dose adjustment is necessary.

Method of administration and doses

The tablets should be swallowed whole with sufficient liquid. The tablets can be taken with or between meals. The drug should be taken at least 2 hours before or after taking iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for didanosine forms containing aluminum or magnesium buffering agents) and sucralfate, as absorption may be reduced.

Children.

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

Overdose

Treatment. In case of overdose, symptomatic treatment should be given. ECG monitoring is necessary, as there is a possibility of prolongation of the QT interval. Antacids can be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and HAPD, are not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions

Adverse reactions are listed below by system organ class and frequency: very common (≥1/10), common (≥1/100,

Infections and infestations: uncommon - fungal infections, including Candida species, proliferation of other resistant microorganisms, disruption of normal intestinal microflora and development of secondary infection.

From the blood and lymphatic system: infrequently - leukopenia, eosinophilia; rarely - thrombocytopenia, neutropenia; unknown - pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: Rare: angioedema, hypersensitivity (see section "Special warnings and precautions for use"); Not known: anaphylactic shock*, anaphylactoid shock* (see section "Special warnings and precautions for use").

On the part of the endocrine system: rarely - syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: infrequently - anorexia; rarely - hypoglycemia, mainly in patients with diabetes (see section "Special warnings and precautions for use"), hypoglycemic coma (see section "Special warnings and precautions for use"); unknown - hyperglycemia (see section "Special warnings and precautions for use").

Psychiatric disorders: often - insomnia; infrequently - anxiety, confusion, nervousness; rarely - psychotic reactions (e.g. with hallucinations, paranoia), depression, agitation, unusual dreams, nightmares, delirium, memory impairment; unknown - psychotic reactions with self-destructive behavior, including suicidal thoughts or actions (see section "Special warnings and precautions for use").

Nervous system***: often - headache, dizziness; infrequently - drowsiness, tremor, dysgeusia; rarely - convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), paresthesia; unknown - peripheral sensory neuropathy (see section "Special warnings and precautions for use"), peripheral sensorimotor neuropathy (see section "Special warnings and precautions for use"), parosmia, including anosmia, dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension.

On the part of the organs of vision***: rarely - visual disturbances, such as blurred vision (see section "Special instructions for use"), unknown - temporary loss of vision (see section "Special instructions for use"), uveitis.

From the organs of hearing and balance***: infrequently - vertigo; rarely - tinnitus; unknown - hearing impairment, hearing loss.

Cardiovascular system****: rarely - tachycardia, palpitations, hypotension; unknown - ventricular tachycardia, which can lead to cardiac arrest, ventricular arrhythmia and torsade de pointes type of torsade de pointes (predominantly in patients with risk factors for QT prolongation), prolongation of the QT interval on the electrocardiogram (see sections "Special instructions" and "Overdose").

On the part of the respiratory system: infrequently - shortness of breath (dyspnea); unknown - bronchospasm, allergic pneumonitis.

Gastrointestinal: often - diarrhea, vomiting, nausea; infrequently - abdominal pain, dyspepsia, bloating, constipation; unknown - hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special instructions for use").