Lebel film-coated tablets 500 mg blister No. 7

Instructions for use Lebel film-coated tablets 500 mg blister No. 7

Composition

active ingredient: levofloxacin;

1 tablet contains levofloxacin 500 mg (as levofloxacin hemihydrate);

excipients: microcrystalline cellulose, hypromellose, crospovidone, sodium stearyl fumarate; Opadry Y1 7000 White coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Dosage form

Film-coated tablets.

Main physicochemical properties: oblong, film-coated tablets, white in color, with a break line 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, 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 MIC breakpoints recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for levofloxacin, which distinguish susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms, are presented in the MIC test 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 it is advisable to obtain local information on resistance, particularly when treating severe infections. As necessary, 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 99-100%.

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 tissues and body 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 relatively 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 insufficiency

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 the following infections in adults caused by levofloxacin-susceptible microorganisms:

acute bacterial sinusitis;

exacerbation of chronic obstructive pulmonary disease, including bronchitis;

community-acquired pneumonia;

complicated skin and soft tissue infections;

uncomplicated cystitis

(in the case of the treatment of the above-mentioned infections, the drug can be used only when the use of other antibacterial agents, which are usually prescribed for the initial treatment of these infections, is impossible);

acute pyelonephritis and complicated urinary tract infections;

chronic bacterial prostatitis;

Pulmonary anthrax: post-exposure prophylaxis and treatment.

Levofloxacin in this dosage form (tablets) can be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin solution for infusion.

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

Contraindication

Hypersensitivity to levofloxacin, other fluoroquinolones or to any component of the drug; epilepsy; tendon damage after previous use of fluoroquinolones; children's age; pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

Antacids containing magnesium and aluminum: medicines containing iron salts, zinc, didanosine.

The absorption of levofloxacin is significantly reduced when used simultaneously with antacids containing magnesium and aluminum, drugs containing iron salts, or with didanosine (didanosine in a buffered tablet with aluminum or magnesium). The simultaneous use of fluoroquinolones with multivitamins containing zinc leads to a decrease in their absorption.

The recommended time interval between taking levofloxacin and the above-mentioned medications should be at least 2 hours.

Calcium salts have minimal effect on the absorption of levofloxacin.

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 levofloxacin (see section "Method of administration and dosage").

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

No pharmacokinetic interaction of levofloxacin with theophylline has been identified. However, a significant decrease in the seizure threshold may occur with the simultaneous use of quinolones with theophylline, NSAIDs and other drugs that lower the seizure threshold. It is known that the concentration of levofloxacin with concomitant administration of fenbufen is approximately 13% higher than with levofloxacin 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 24% when co-administered with cimetidine and by 34% when co-administered with probenecid. This is because both drugs are capable of blocking the tubular secretion of levofloxacin. Levofloxacin should be used with caution simultaneously with drugs that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal insufficiency.

Other medicines

Calcium carbonate, digoxin, glibenclamide, and ranitidine do not have a clinically significant effect on the pharmacokinetics of levofloxacin when used simultaneously.

Effect of the drug on other medicines

Cyclosporine

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

Vitamin K antagonists

Concomitant use with vitamin K antagonists (e.g. warfarin) may increase coagulation tests (PT/international normalized ratio) and/or bleeding, which may be severe. Therefore, coagulation tests 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, such as class IA and III antiarrhythmics, tricyclic antidepressants and macrolides, antipsychotic medicinal products (see section "Special warnings and precautions for use" ("QT interval prolongation")).

Levofloxacin does not affect the pharmacokinetics of theophylline, which is predominantly metabolized by CYP1A2, therefore it can be assumed that levofloxacin is not a CYP1A2 inhibitor.

Other forms of interaction

Eating

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

Application features

The drug should be avoided in patients who have had serious adverse reactions to quinolones or fluoroquinolones in the past. Levofloxacin should only be initiated in these patients if no alternative treatment options are available and after a careful benefit/risk assessment.

Resistance.

In very severe pneumonia caused by pneumococci, levofloxacin may not have an optimal therapeutic effect.

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

Methicillin-resistant S. aureus

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 the susceptibility of the microorganism to levofloxacin is confirmed.

Levofloxacin can be prescribed for the treatment of acute bacterial sinusitis and exacerbation of chronic bronchitis with adequate diagnosis of these diseases.

Levofloxacin-resistant Escherichia coli may be the most common causative agent of urinary tract infections, which should be considered when prescribing levofloxacin to patients with urinary tract diseases. When prescribing fluoroquinolones, the local prevalence of Escherichia coli resistance to fluoroquinolones should be taken into account.

In the case of pulmonary anthrax, use is based on in vitro susceptibility data of Bacillus anthracis and experimental animal data, as well as limited human data. Physicians should consider national and/or international consensus documents on the treatment of anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions

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

Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes lateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and even up to several months after stopping treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of developing tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients with solid organ transplants 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

Diarrhoea, particularly severe, persistent or bloody during or after treatment (including several weeks after treatment) with levofloxacin, 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. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and patients should be treated urgently with supportive measures and specific therapy (e.g. oral vancomycin) may be required. Anti-motility agents are contraindicated in this clinical situation.

Patients prone 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 prone to seizures, in particular in patients with previous central nervous system lesions, with concomitant therapy with fenbufen and similar NSAIDs or drugs that increase seizure readiness (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other types of interactions"). If seizures occur, treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or present defects in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with antibacterial agents of the quinoline group, therefore levofloxacin should be used with caution in them.

Patients with renal insufficiency

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 may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to and including anaphylactic shock) after the initial dose (see section 4.8). In such cases, patients should discontinue treatment immediately and consult a doctor.

Severe skin adverse reactions

Serious skin reactions such as toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with levofloxacin, which can be life-threatening or fatal (see section 4.8). Patients should be advised of the signs and symptoms of these serious skin reactions and monitored closely when prescribing the medicinal product. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment should be considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome, TEN or DRESS with levofloxacin, levofloxacin should not 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 hypoglycaemia and cases of hyperglycaemia, usually in diabetic patients receiving concomitant therapy with an oral hypoglycaemic agent (e.g. glibenclamide) or insulin. Cases of hypoglycaemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section 4.8).

Prevention of photosensitivity

Although photosensitivity occurs very rarely with levofloxacin, in order to avoid it, patients are advised not to unnecessarily expose themselves to strong sunlight or artificial UV radiation (e.g. artificial ultraviolet lamps, solarium) due to possible photosensitivity while taking levofloxacin or for 48 hours after stopping levofloxacin.

Due to the possible increase in coagulation tests (PT/international normalized ratio) and/or bleeding in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored (see section 4.5).

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In rare cases, these reactions have progressed to suicidal ideation and self-harm, sometimes even after 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 and in patients with 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;

concomitant use of drugs known to prolong the QT interval (such as class IA and III antiarrhythmics, tricyclic antidepressants, macrolides);

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

old age;

heart disease (e.g., heart failure, myocardial infarction, bradycardia);

concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics); elderly patients and women are more sensitive to drugs that prolong the QT interval, therefore caution should be exercised when using fluoroquinolones, including levofloxacin, in these categories of patients (see sections "Interaction with other medicinal products and other types of interactions", "Method of administration and dosage" ("Elderly patients"), "Overdose", "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients taking the drug should inform their physician or prevent the development of a potentially irreversible condition.

Hepatobiliary disorders

Cases of necrotizing hepatitis, up to life-threatening 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 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 period, 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.

Vision 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

When using levofloxacin, especially long-term, the development of opportunistic infections and the growth of resistant microorganisms is possible. If a secondary infection develops, appropriate measures should be taken.

Laboratory studies

In patients treated with levofloxacin, urine opiates may give false-positive results. Positive results for opiates may need to be confirmed by 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

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

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

Pregnancy: There are limited data from the use of levofloxacin in pregnant women.

Due to the lack of human studies and the possible damage of quinolones to articular cartilage in the growing body, levofloxacin is contraindicated in pregnant and lactating women. If pregnancy occurs during treatment with the drug, the doctor should be informed.

Breastfeeding. Levofloxacin is contraindicated during 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 possible damage of fluoroquinolones to articular cartilage in the growing body, levofloxacin should not be prescribed to women who are breastfeeding.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients who drive vehicles, work with machines and mechanisms should take into account possible adverse reactions from the nervous system (dizziness, drowsiness, confusion, visual and hearing disorders, disorders of movement processes, including when walking), which impair the patient's ability to concentrate or speed of reaction.

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.

Method of administration and doses

Tablets should be taken 1 or 2 times a day. The dose 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 confirmed destruction of pathogens by microbiological tests.

The tablets should be swallowed whole with a sufficient amount of liquid. For ease of dosing, the tablet can be divided using the score line. They can be taken with or without food.

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.

Adult patients with normal renal function (creatinine clearance above 50 ml/min) should follow the following recommendations:

Dosage for patients with renal impairment whose creatinine clearance is less than 50 ml/min:

*Use in appropriate dosage.

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 in elderly patients: If renal function is not impaired, no dose adjustment is required (see section "Special warnings and precautions for use" ("Tendinitis and tendon ruptures", "QT prolongation")).

Children.

The use of the drug is contraindicated in children, 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

The frequency of side effects was determined using 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 unknown (cannot be estimated from the available data).

Within each group, adverse reactions are presented in order of decreasing seriousness.

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; frequency unknown - pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: Rare: angioedema, hypersensitivity (see section "Special warnings and precautions for use"); Frequency unknown: anaphylactic/anaphylactoid shock (see section "Special warnings and precautions for use").

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

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

Nervous system disorders*: common: headache, dizziness; uncommon: drowsiness, tremor, dysgeusia (subjective taste disturbance); rare: convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), paresthesia; frequency unknown: peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), olfactory impairment (parosmia), including anosmia (absence of smell), dyskinesia (impaired coordination of movements), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hemorrhage (including cranial hemorrhage), convulsions (including cranial hemorrhage), paresthesia (including cranial hemorrhage), peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), olfactory impairment (parosmia), including anosmia (absence of smell), dyskinesia (impaired coordination of movements), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hemorrhage (including cranial hemorrhage), peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or motor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or motor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or motor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or motor neuropathy (see section "Special warnings and precautions for use"), peripheral sensory or motor neuropathy (see section