Levofloxacin film-coated tablets 500 mg No. 10

Instructions Levofloxacin film-coated tablets 500 mg No. 10

Composition

active ingredient: 1 tablet contains 256.23 mg of levofloxacin hemihydrate, which is equivalent to 250 mg of levofloxacin;

1 tablet contains 512.46 mg of levofloxacin hemihydrate, which is equivalent to 500 mg of levofloxacin;

excipients: hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate, polyethylene glycol 6000, talc, red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, film-coated tablets, light pink to light brown in color with a pink tint, with convex upper and lower surfaces.

On the fracture, under a magnifying glass, a light yellow or yellowish-white core is visible, surrounded by one continuous layer.

Pharmacotherapeutic group

Antibacterials for systemic use. Fluoroquinolones. Levofloxacin.

ATX code J01M A12.

Pharmacological properties

Pharmacodynamics

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

Mechanism of action. Levofloxacin, as an antibacterial drug from the fluoroquinolone group, acts on the DNA gyrase and topoisomerase IV complex.

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

Mechanism of resistance: Resistance to levofloxacin develops in a stepwise process due to target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other mechanisms of resistance, such as the impermeable barrier (common in Pseudomonas aeruginosa) and the efflux mechanism, may also influence levofloxacin susceptibility.

Due to its mechanism of action, there is usually no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints. 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 testing table below (mg/L).

EUCAST MIC clinical breakpoints for levofloxacin (version 2.0, 2012-01-01):

Antibacterial spectrum. The prevalence of resistance may vary geographically and over time for selected species, and local information on resistance is desirable, particularly when treating severe infections. Specialist advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

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

Pharmacokinetics

Absorption.

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations occurring within 1 hour. Absolute bioavailability is approximately 100%.

Food has almost no effect on the absorption of levofloxacin.

Steady state is achieved within 48 hours with a dosage regimen of 500 mg 1-2 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 a single and repeated dose of 500 mg, indicating good distribution into body tissues.

Penetration into body tissues and fluids.

Levofloxacin has the ability to penetrate the bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (blister contents), prostate tissue and urine. Levofloxacin penetrates poorly into the cerebrospinal fluid.

Biotransformation.

Levofloxacin is metabolized to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the drug excreted in the urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Breeding.

After oral and intravenous administration, levofloxacin is eliminated from the blood plasma slowly (half-life is 6-8 hours). The 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, which indicates the interchangeability of these routes (oral and intravenous).

Linearity.

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

Patients with renal failure.

The pharmacokinetics of levofloxacin are affected by renal insufficiency. With decreased renal function, renal excretion and creatinine clearance decrease, and the half-life 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

Levofloxacin is indicated for the treatment of infections caused by levofloxacin-susceptible microorganisms in adults:

acute bacterial sinusitis;

exacerbation of chronic obstructive pulmonary disease, including bronchitis;

community-acquired pneumonia;

complicated skin and soft tissue infections;

uncomplicated cystitis.

In the treatment of the above infections, the drug is used only when the use of other antibacterial agents, which are usually prescribed for the initial treatment of these infections, is not possible.

Complicated urinary tract infections (including acute pyelonephritis);

chronic bacterial prostatitis;

Pulmonary anthrax: post-exposure prophylaxis and treatment.

This dosage form of levofloxacin can be used to complete a course of therapy in patients who have demonstrated improvement during initial treatment with levofloxacin in the form of a solution for infusion.

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

Contraindication

Hypersensitivity to levofloxacin, other fluoroquinolones or to any of the excipients of the drug;

epilepsy;

tendon damage associated with the use of fluoroquinolones;

childhood (up to 18 years old);

pregnancy and breastfeeding.

Interaction with other medicinal products and other types of interactions

Effects of other drugs on levofloxacin.

The absorption of levofloxacin is significantly reduced when iron salts, magnesium or aluminum antacids or didanosine (this applies only to didanosine dosage forms with aluminum or magnesium-containing buffering agents) are used simultaneously with the drug. The simultaneous use of fluoroquinolones and multivitamin preparations containing zinc reduces their absorption after oral administration. It is not recommended to use drugs containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium or aluminum-containing antacids or didanosine (this applies only to didanosine dosage forms with aluminum or magnesium-containing buffering agents), within 2 hours before or after taking the drug (see section "Method of administration and dosage"). Calcium salts have a minimal effect on the absorption of levofloxacin after oral administration.

Sucralfate.

The bioavailability of levofloxacin tablets is significantly reduced when the drug is used concomitantly with sucralfate. If the patient needs to receive both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after taking the drug (see section "Method of administration and dosage").

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

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 and NSAIDs 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 statistically significant effects on the elimination of levofloxacin. The renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both drugs are capable of blocking the tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that the statistically significant kinetic differences are of clinical relevance. Caution should be exercised when levofloxacin is co-administered with drugs that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information.

The following drugs have no clinically significant effect on the pharmacokinetics of levofloxacin when used concomitantly: calcium carbonate, digoxin, glibenclamide, ranitidine.

The effect of levofloxacin on other drugs.

Cyclosporine.

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

Vitamin K antagonists.

When used concomitantly with vitamin K antagonists (e.g. warfarin), increases in coagulation tests (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 4.4).

Drugs 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 antipsychotics) (see section 4.4 (QT prolongation)).

Other significant information.

There is no evidence of an effect of levofloxacin on the pharmacokinetics of theophylline (which is a substrate of the CYP1A2 enzyme), indicating that levofloxacin is not a CYP1A2 inhibitor.

Other forms of interaction. Eating.

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

Application features

Levofloxacin should be avoided in patients who have had a serious adverse reaction to a quinolone or fluoroquinolone-containing product in the past (see section 4.8). Levofloxacin should only be initiated in these patients if no alternative treatment options are available and after a careful benefit/risk assessment (see section 4.8).

The benefits of treatment with levofloxacin, especially in the case of non-serious infections, should be assessed taking into account the information contained in this section.

Prolonged, disabling and potentially irreversible serious adverse reactions.

In very rare cases, prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting different, and sometimes multiple, body systems (including musculoskeletal, nervous, mental and sensory) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age or existing risk factors. The drug should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and a doctor should be consulted.

Methicillin-resistant S. Aureus (MRSA) has a very high probability of being co-resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, unless laboratory tests have 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 E. coli (the most common cause of urinary tract infections) varies between countries. The local prevalence of fluoroquinolone resistance in E. coli should be taken into account when prescribing fluoroquinolones.

Pulmonary form of anthrax.

The use of the drug in humans is based on in vitro susceptibility data of Bacillus anthracis and experimental animal data, together with limited data on its use in humans. Physicians should refer to national and/or international consensus guidelines for the treatment of anthrax.

Tendinitis and tendon rupture.

Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur as early as 48 hours after initiation of treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplantation and patients receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation), treatment with the drug 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.

Diseases caused by Clostridium difficile.

Diarrhea, particularly severe, persistent and/or bloody, occurring during or after treatment with levofloxacin (including within a few weeks after treatment), may be a symptom of Clostridium difficile disease. The most severe form of this disease is pseudomembranous colitis (see section "Adverse reactions"). In this regard, the physician should consider the possibility of Clostridium difficile disease if a patient develops severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile disease is suspected, levofloxacin should be immediately discontinued and appropriate treatment should be initiated as a matter of urgency. Drugs that inhibit intestinal motility are contraindicated in this case.

Patients with a tendency to seizures.

Quinolones may lower the seizure threshold and precipitate seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, like other quinolones, should be used with extreme caution in patients prone to seizures and in concomitant treatment with active substances that lower the seizure threshold, such as theophylline (see section 4.5). Levofloxacin should be discontinued if a seizure occurs (see section 4.8).

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be predisposed to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin is necessary, these patients should be monitored for possible hemolysis.

Patients with renal failure.

Since levofloxacin is excreted mainly by the kidneys, dose adjustment is required for patients with impaired renal function (renal failure) (see section "Method of administration and dosage").

Hypersensitivity reactions.

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema to anaphylactic shock), in some cases after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, a doctor should be consulted and appropriate treatment should be initiated.

Severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with levofloxacin (see section 4.8). Patients should be advised of the signs and symptoms of severe skin reactions and monitored closely during treatment. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. If a patient has developed a serious reaction such as SJS, TEN or DRESS with levofloxacin, levofloxacin should never be restarted in that patient.

Change in blood glucose levels.

As with all quinolones, cases of changes in blood glucose levels have been reported, including both cases of hypoglycemia and cases of hyperglycemia, usually observed in diabetic patients receiving concomitant therapy with an oral hypoglycemic agent (e.g. glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section 4.8).

Prevention of photosensitization.

Photosensitivity has been reported with levofloxacin (see section 4.8). To prevent photosensitivity, it is recommended that patients avoid unnecessary exposure to strong sunlight or artificial sources of UV light (e.g., sunlamps, tanning beds) during treatment and for 48 hours after stopping levofloxacin.

Patients receiving vitamin K antagonists.

Due to the possible increase in blood coagulation parameters (prothrombin time/international normalized ratio) and/or an increase in the frequency of hemorrhagic complications in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), blood coagulation parameters should be monitored during concomitant use of these agents (see section "Interaction with other medicinal products and other types of interactions").

Psychotic reactions.

Psychotic reactions have been reported in patients receiving quinolines, including levofloxacin. In very rare cases, these have progressed to suicidal ideation and self-harming behaviour, sometimes after only a single dose of levofloxacin (see section 4.8). If a patient develops 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 or acquired long QT syndrome;

simultaneous use of drugs that have the ability to prolong the QT interval (for example, class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotic drugs);

electrolyte imbalance (e.g. hypokalemia, hypomagnesemia);

heart disease (e.g. heart failure, myocardial infarction, bradycardia). (see sections “Method of administration and dosage (Elderly patients)”, “Interaction with other medicinal products and other types of interactions”, “Adverse reactions”, “Overdose”).

Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patients.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones. Patients receiving quinolones should be advised to inform their physician if they experience symptoms of neuropathy, such as pain, burning, tingling, numbness, or weakness, to prevent the development of a potentially irreversible condition.

Hepatobiliary disorders.

Cases of hepatic necrosis up to and including fatal hepatic failure have been reported with levofloxacin (predominantly in patients with severe underlying diseases such as sepsis) (see section 4.8). Patients should be advised to discontinue treatment and seek medical advice 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, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing setting, serious adverse reactions, including fatalities and conditions requiring respiratory support, have been associated with the use of fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, especially in elderly patients, and of aortic and mitral valve regurgitation after the use of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and of regurgitation/insufficiency of any of the cardiac valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with a positive family history of aneurysm or congenital heart valve disease, or in patients with an existing diagnosis of aortic aneurysm and/or dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

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

in aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome) or additionally

in case of regurgitation/valvular insufficiency (e.g. infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving concomitant systemic corticosteroids.

Patients should seek immediate medical attention in the emergency department if they experience sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical attention in the event of acute shortness of breath, new onset of palpitations, or development of abdominal or lower extremity edema.

Visual impairment.

If any visual disturbances or adverse reactions from the visual organs occur while taking levofloxacin, you should immediately consult an ophthalmologist (see sections “Ability to affect the speed of reactions when driving vehicles or using other mechanisms” and “Adverse reactions”).

Superinfection.

The use of levofloxacin, especially long-term, may lead to overgrowth of non-susceptible (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. Positive opiates from screening tests may need to be confirmed by more specific methods.

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

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

Use during pregnancy or breastfeeding

Due to the lack of studies and the possible damage of quinolones to articular cartilage in a growing body, the drug is contraindicated for pregnant and breastfeeding women. If pregnancy is diagnosed during treatment with the drug, the doctor should be informed.

Levofloxacin did not impair fertility or 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

Levofloxacin tablets are taken 1–2 times a day. The dose depends on the type, severity of the infection, and the sensitivity of the likely pathogen.

The duration of treatment depends on the course of the disease and is no more than 14 days. It is recommended to continue using the drug for at least 48–72 hours after normalization of body temperature or confirmed destruction of pathogens by microbiological tests.

Levofloxacin tablets should be swallowed whole, without chewing, with sufficient liquid. Tablets can be taken regardless of meals.

The drug should be administered at least 2 hours before or after the use of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for forms containing aluminum or magnesium in buffering agents) and sucralfate (see section "Interaction with other medicinal products and other types of interactions").

Tablets can be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin in the form of a solution for infusion, using the same dosages.

Table 1

Recommended dosage for adult patients with normal renal function, with creatinine clearance greater than 50 mL/min

Special populations

Table 2

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

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

Dosage for patients with hepatic impairment: No dosage adjustment is required since levofloxacin is only slightly metabolized in the liver and is excreted primarily by the kidneys.

Dosage for elderly patients: If renal function is not impaired, no dose adjustment is required (see section "Special warnings and precautions for use").

Children

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

Overdose

According to animal toxicity studies or clinical pharmacology studies conducted at doses higher than therapeutic, the most important signs to be expected after acute overdose of levofloxacin are central nervous system symptoms such as confusion, dizziness, impaired consciousness and seizures, QT prolongation, and gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, central nervous system effects including confusion, convulsions, hallucinations and tremor have been observed.

In case of overdose, symptomatic treatment should be carried out. 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.

Side effects

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

From the blood and lymphatic system: leukopenia, eosinophilia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia, thrombocytopenia, which may cause an increased tendency to hemorrhage or bleeding.

Immune system: hypersensitivity reactions, including anaphylactic/anaphylactoid shock1, may occur even after the first dose within minutes or hours after administration (see section "Special warnings and precautions for use"); angioedema, urticaria, bronchospasm, wheezing, skin and mucous membrane swelling, sudden decrease in blood pressure, shock.

Metabolism and nutrition: anorexia, lack of appetite, hypoglycemia, especially in patients with diabetes (see section "Special instructions"), hyperglycemia, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, increased sweating, tremor of the limbs.

Nervous system*: headache, dizziness, confusion