Instructions Levoximed film-coated tablets 500 mg blister No. 7
Composition
active ingredient: levofloxacin;
1 tablet contains levofloxacin (in the form of levofloxacin hemihydrate) 500 mg;
excipients: microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
film coating composition: Opadry II yellow (85G32281): polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, lecithin, iron oxide yellow (E 172), IA63400/IC07484 talc/iron oxide red (E 172) (3:1).
Dosage form
Film-coated tablets.
Main physicochemical properties: oblong, film-coated tablets, light peach in color with a score line on one side.
Pharmacotherapeutic group
Antibacterials of the quinolone group. Fluoroquinolones. ATX code J01M A12.
Pharmacological properties
Pharmacodynamics
Levoximed is a broad-spectrum antimicrobial agent from the group of fluoroquinolones, a levorotatory isomer of ofloxacin - L-ofloxacin. By inhibiting DNA gyrase and topoisomerase IV, it disrupts the process of bacterial DNA formation.
Mechanism of resistance development
Resistance to levofloxacin develops by stepwise mutation of the target site in both types of topoisomerase II, DNA gyrase and topoisomerase IV. Other mechanisms of resistance, such as permeability (specific to Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to levofloxacin. Cross-resistance has been observed between levofloxacin and other fluoroquinolones. Due to the mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents. The prevalence of resistance may vary geographically and over time for individual species, therefore local information on resistance is very important, especially in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the appropriateness of the agent in some types of infections is questionable.
Antibacterial spectrum
| Typically sensitive species |
| Gram-positive aerobes: |
| Bacillus anthracis |
| Staphylococcus aureus methicillin-sensitive |
| Staphylococcus saprophyticus |
| Streptococci, groups C and G |
| Streptococcus agalactiae |
| Streptococcus pneumoniae |
| Streptococcus pyogenes |
| Gram-negative aerobes: |
| Eikenella corrodens |
| Haemophilus influenzae |
| Haemophilus parainfluenzae |
| Klebsiella oxytoca |
| Moraxella catarrhalis |
| Pasteurella multocida |
| Proteus vulgaris |
| Providencia rettgeri |
| Anarob: |
| Peptostreptococcus |
| Others: |
| Chlamydophila pneumoniae |
| Chlamydophila psittaci |
| Chlamydia trachomatis |
| Legionella pneumophila |
| Mycoplasma pneumoniae |
| Mycoplasma hominis |
| Ureaplasma urealyticum |
| Species with possible acquired resistance |
| Gram-positive aerobes: |
| Enterococcus faecalis |
| Staphylococcus aureus methicillin-resistant 1 |
| Coagulase-negative Staphylococcus spp |
| Gram-negative aerobes: |
| Acinetobacter baumannii |
| Citrobacter freundii |
| Enterobacter aerogenes |
| Enterobacter cloacae |
| Escherichia coli |
| Klebsiella pneumoniae |
| Morganella morganii |
| Proteus mirabilis |
| Providencia stuartii |
| Pseudomonas aeruginosa |
| Serratia marcescens |
| Anaerobes: |
| Bacteroides fragilis |
| Naturally resistant strains |
| Gram-positive aerobes: |
| Enterococcus faecium |
1 Methicillin-resistant Staphylococcus aureus is most likely to be co-resistant to fluoroquinolones, including levofloxacin.
Pharmacokinetics
Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 600 mg. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.
Absorption
After oral administration, levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations occurring within 1–2 hours. Absolute bioavailability is 99–100%. Food intake has a slight effect on absorption. Steady-state values are reached within 48 hours after administration of 500 mg of levofloxacin 1–2 times daily.
Distribution
Approximately 30–40% of levofloxacin is bound to plasma proteins. The mean volume of distribution of levofloxacin is about 100 l after a single and repeated dose of 500 mg, which indicates good distribution in body tissues (bronchial mucosa, sputum, alveolar macrophages, skin, lung tissue, prostate tissue, urine). It penetrates poorly into the cerebrospinal fluid.
Metabolism
Levofloxacin is metabolized to a minor extent. The metabolites are desmethyl-levofloxacin and levofloxacin N-oxide, which account for less than 5% of the amount of drug excreted in the urine.
Breeding
After oral administration, levofloxacin is eliminated from the blood plasma relatively slowly (half-life 6–8 hours). Excretion is mainly renal (more than 85% of the administered dose).
Renal impairment affects the pharmacokinetics of levofloxacin. As renal function decreases, excretion and clearance decrease, and the half-life increases (see Table 1).
| Creatinine clearance (ml/min) | < 20 | 20-40 | 50-80 |
| Renal clearance (ml/min) | 13 | 26 | 57 |
| Half-life (hours) | 35 | 35 | 35 |
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 differences in the pharmacokinetics of levofloxacin based on gender. There is no evidence that these gender differences are clinically relevant.
Indication
Treatment of the following infections caused by microorganisms susceptible to levofloxacin:
acute bacterial sinusitis; acute exacerbation of chronic bronchitis; community-acquired pneumonia; complicated skin and soft tissue infections.
Treatment of the following infections when other antibacterial agents usually prescribed for the initial treatment of these infections are not possible:
Complicated urinary tract infections (including pyelonephritis); chronic bacterial prostatitis; uncomplicated cystitis; pulmonary anthrax (post-exposure prophylaxis and treatment).
The drug can be used to complete a course of therapy in patients who have demonstrated improvement during initial treatment with levofloxacin for injection.
Official recommendations on the appropriate use of antibacterial agents should be considered.
Contraindication
Hypersensitivity to levofloxacin, other fluoroquinolones or to any of the other components of the drug.
Epilepsy.
Tendon damage associated with previous use of fluoroquinolones.
Children's age (up to 18 years).
Pregnancy.
Breastfeeding period.
Interaction with other medicinal products and other types of interactions
Iron salts, zinc salts, antacids containing magnesium and aluminum, didanosine.
Levofloxacin absorption may be significantly reduced when administered concomitantly with iron salts and antacids containing magnesium or aluminum, didanosine (only for forms containing aluminum or magnesium buffering agents). Concomitant administration of fluoroquinolones with multivitamins containing zinc results in reduced oral absorption. Levofloxacin should be administered at least 2 hours after administration of drugs containing divalent or trivalent cations, such as iron salts, or antacids containing magnesium or aluminum. Calcium carbonate had minimal effect on oral absorption of levofloxacin.
Sucralfate
There may be a significant reduction in the bioavailability of levofloxacin when used concomitantly. Sucralfate should be taken 2 hours after levofloxacin.
Theophylline, fenbufen or similar nonsteroidal anti-inflammatory drugs (NSAIDs), other agents that lower the seizure threshold
A significant decrease in the seizure threshold is possible when they are used simultaneously. No pharmacokinetic interaction of levofloxacin with theophylline was found. The concentration of levofloxacin when used with fenbufen was approximately 13% higher than when levofloxacin was taken alone.
Probenecid, cimetidine and other agents that affect tubular secretion
Levofloxacin elimination may be reduced (due to inhibition of its tubular secretion) when used concomitantly. Renal clearance of levofloxacin is reduced by 24% with cimetidine and 34% with probenecid. However, in the study, statistically significant kinetic differences were not clinically significant. Levofloxacin should be used with caution when used concomitantly with agents that affect tubular secretion, especially in patients with renal insufficiency.
Cyclosporine
The half-life of cyclosporine increases by 33%.
Vitamin K antagonists
Coagulation monitoring should be performed when levofloxacin is used concomitantly with vitamin K antagonists (e.g. warfarin). Elevated international normalized ratio and/or bleeding, which may be severe, have been reported.
QT prolonging agents
Concomitant use of levofloxacin with drugs that may prolong the QT interval (e.g. class IA and III antiarrhythmics, tricyclic antidepressants, macrolides and antipsychotics) may prolong the QT interval. Caution should be exercised when levofloxacin is used concomitantly with drugs that may prolong the QT interval (e.g. class IA and III antiarrhythmics, tricyclic antidepressants, macrolides and antipsychotics).
Other interactions:
No effect of levofloxacin was recorded when used simultaneously with calcium carbonate, digoxin, glibenclamide, ranitidine.
No effect of levofloxacin on the pharmacokinetics of theophylline (which is a marker substrate for the CYP1A2 enzyme) was observed, indicating that levofloxacin is not a CYP1A2 inhibitor.
Impact on laboratory tests
Levofloxacin inhibits the growth of Mycobacterium tuberculosis, therefore a false-negative result is possible when conducting bacteriological studies in patients with tuberculosis.
Application features
Methicillin-resistant Staphylococcus aureus (MRSA) has a very high probability of being co-resistant to fluoroquinolones, including levofloxacin. Therefore, the drug is not recommended for the treatment of infections known or suspected to be caused by MRSA, unless laboratory tests have confirmed the susceptibility of the pathogen to levofloxacin.
The drug can be used to treat acute bacterial sinusitis and exacerbation of chronic bronchitis, if these infections have been diagnosed appropriately.
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.
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 data on use in humans. Physicians should consider national and/or international consensus documents on the treatment of anthrax.
Tendinitis and tendon ruptures
Tendinitis, which may lead to tendon rupture, including Achilles tendon, may occur with the use of quinolones, including levofloxacin. Tendinitis and tendon rupture, sometimes bilateral, may occur 48 hours after levofloxacin administration and even several months after discontinuation of its use. Patients over 60 years of age, patients receiving a daily dose of 1000 mg of levofloxacin, as well as patients treated with corticosteroids are most susceptible to tendinitis and tendon rupture. In elderly patients, the daily dose should be adjusted taking into account creatinine clearance and their condition should be monitored. If tendinitis is suspected, the drug should be discontinued immediately and appropriate treatment should be initiated (e.g., immobilization of the tendon).
Diseases caused by Clostridium difficile
Diarrhoea, particularly severe, persistent and/or haemorrhagic, during or after the use of levofloxacin (even within several weeks of treatment) may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. Clostridium difficile-associated disease 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 severe diarrhoea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, the drug should be discontinued immediately and appropriate treatment should be initiated immediately. Anti-peristaltic agents are contraindicated in this clinical situation.
Hypersensitivity reactions
Serious, potentially fatal hypersensitivity reactions (ranging from angioedema to anaphylactic shock) may occur with levofloxacin, even after the first dose. If such reactions occur, the drug should be discontinued immediately, a doctor should be consulted and appropriate treatment should be initiated.
Severe bullous reactions
Severe bullous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with levofloxacin, even after the first dose. If skin and mucosal reactions occur, the drug should be discontinued immediately, a doctor should be consulted and appropriate treatment should be initiated.
Metabolic disorders
Changes in blood glucose levels (hyperglycemia, hypoglycemia) have been reported with the use of quinolones, including levofloxacin, especially in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. During the use of the drug in diabetic patients, plasma glucose levels should be monitored.
Photosensitization
Photosensitivity may occur in rare cases during the use of levofloxacin. Patients are advised not to expose themselves to strong sunlight or artificial UV radiation (e.g. artificial ultraviolet lamps, solariums) during use of the drug and for 48 hours after discontinuation of its use.
Psychotic disorders
Psychotic reactions have been reported with 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 develops these reactions, the drug should be discontinued and appropriate measures should be taken. The drug should be used with caution in patients with psychotic disorders or in patients with a history of psychiatric illness.
QT prolongation
The drug should be used with caution in patients with known risk factors for QT prolongation, such as:
concomitant use of drugs known to prolong the QT interval (e.g. class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia);
heart disease (e.g., heart failure, myocardial infarction, bradycardia).
Female patients and elderly patients may be more sensitive to drugs that prolong the QT interval. The drug should be used with caution in these categories of patients.
Peripheral neuropathies
Peripheral sensory or sensorimotor neuropathy, which may be rapid in onset, has been reported with quinolones, including levofloxacin, in patients receiving fluoroquinolones, including levofloxacin. The drug should be discontinued if a patient develops symptoms of neuropathy to prevent the development of an irreversible condition.
Genitourinary 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. The drug should be discontinued and a doctor consulted if signs and symptoms of liver disease such as anorexia, jaundice, dark urine, itching 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 post-marketing experience with fluoroquinolones in patients with myasthenia gravis. The drug is not recommended for use in patients with a history of myasthenia gravis.
Vision impairment
If visual impairment or other effects on the eyes are observed while using the drug, you should immediately consult an ophthalmologist.
Superinfection
When using levofloxacin, especially long-term, the development of opportunistic infections and the growth of resistant microorganisms is possible. If superinfection develops during the use of the drug, appropriate measures should be taken.
Use in patients prone to seizures
The drug is contraindicated in patients with a history of epilepsy. As with other quinolones, the drug should be used with extreme caution in patients prone to seizures, such as patients with central nervous system lesions, with concomitant therapy with fenbufen and similar NSAIDs or agents that increase seizure readiness (lower the seizure threshold), such as theophylline. If seizures occur, treatment with the drug should be discontinued.
Use in patients with glucose-6-phosphate dehydrogenase deficiency
Patients with latent or present defects in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibacterial agents, so the drug should be used with caution and monitored for possible hemolysis.
Use in patients with renal impairment
Since levofloxacin is excreted primarily by the kidneys, dose adjustment is required for patients with impaired renal function (renal failure).
Ability to influence reaction speed when driving vehicles or other mechanisms
When using the drug, adverse reactions from the nervous system (dizziness/vertigo, drowsiness, visual impairment) may develop, which may reduce the ability to concentrate and the speed of psychomotor reactions, which should be taken into account when driving vehicles or other mechanisms.
Use during pregnancy or breastfeeding
Pregnancy
Data on the use of levofloxacin in pregnant women are limited.
Due to the lack of human studies and the possible damage of quinolones to articular cartilage in the growing body, the drug is contraindicated during pregnancy. If pregnancy occurs during treatment with the drug, the doctor should be informed.
Breastfeeding period
There is insufficient data on the excretion of levofloxacin into breast milk, although other fluoroquinolones are excreted in breast milk. Due to the lack of studies in humans and the possible damage of fluoroquinolones to articular cartilage in a growing organism, the drug is contraindicated during breastfeeding.
Fertility
Levofloxacin did not cause impairment of fertility and reproductive function in animals.
Method of administration and doses
The drug is intended for oral use. The tablets should be swallowed without chewing, with sufficient liquid. The drug can be taken regardless of food intake.
The drug should be used 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.
The drug can be used to complete the course of therapy in patients who have demonstrated improvement during initial treatment with levofloxacin, solution for infusion, using the same dosages.
The dose depends on the type, severity of the infection and the sensitivity of the probable pathogen.
Patients with normal renal function (creatinine clearance above 50 ml/min)
Indication
| Daily dose (depending on severity) | Duration of treatment (depending on severity) | |
| Acute bacterial sinusitis | 500 mg once daily | 10–14 days |
| Exacerbation of chronic bronchitis | 500 mg once daily | 7–10 days |
| Community-acquired pneumonia | 500 mg 1–2 times a day | 7–14 days |
| Pyelonephritis | 500 mg once daily | 7–10 days |
| Complicated urinary tract infections including pyelonephritis | 500 mg once daily | 7–14 days |
| Uncomplicated cystitis | 250 mg once daily | 3 days |
| Chronic bacterial prostatitis | 500 mg once daily | 28 days |
| Complicated skin and soft tissue infections | 500 mg 1–2 times a day | 7–14 days |
| Pulmonary anthrax | 500 mg once daily | 8 weeks |
Patients with impaired renal function (creatinine clearance less than 50 ml/min)
| Dosage regimen (depending on the severity of the infection and the nosological form) | | |
| 250 mg/24 hours | 500 mg/24 hours | 500 mg/12 hours | |
| Creatinine clearance | first dose – 250 mg; | first dose – 500 mg; | first dose – 500 mg; |
| 50–20 ml/min | subsequent - 125 mg/24 hours | subsequent - 250 mg/24 hours | subsequent - 250 mg/12 hours |
| 19–10 ml/min | subsequent - 125 mg/48 hours | subsequent - 125 mg/24 hours | subsequent - 125 mg/12 hours |
| < 10 ml/min (also on hemodialysis and HAPD1) | subsequent - 125 mg/48 hours | subsequent - 125 mg/24 hours | subsequent - 125 mg/24 hours |
1 No additional doses are required after hemodialysis or chronic ambulatory peritoneal dialysis (CHAPD).
Patients with liver dysfunction
No dose adjustment is required for such patients, as levofloxacin is metabolized to a minor extent in the liver and excreted mainly by the kidneys.
Elderly patients
If renal function is not impaired, there is no need for dose adjustment in such patients.
Children
The drug is contraindicated in children (under 18 years of age).
Overdose
Symptoms: central nervous system disorders (confusion, dizziness, impaired consciousness and seizures, hallucinations and tremor); digestive system disorders (nausea and erosion of mucous membranes); possible prolongation of the QT interval.
Treatment: symptomatic therapy. ECG monitoring should be carried out, as QT interval prolongation is possible. Antacids are used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis or HAPD, is not effective in removing levofloxacin from the body. There is no specific antidote.
Adverse reactions
The frequency of adverse reactions was determined using the following criteria: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (> 1/10,000), unknown (cannot be estimated from the available data).
Infections and infestations:
uncommon - fungal infections (including Candida species), proliferation of other resistant microorganisms.
From the blood and lymphatic system:
infrequently - leukopenia, eosinophilia; rarely - neutropenia, thrombocytopenia; unknown - agranulocytosis, hemolytic anemia, pancytopenia.
On the part of the immune system:
Rare: hypersensitivity reactions, including angioedema; Not known: anaphylactic/anaphylactoid shock.
Metabolism and nutrition:
uncommon – anorexia; rare – hypoglycemia (mainly in patients with diabetes mellitus); unknown – hyperglycemia, hypoglycemic coma.
From the psyche:
often - insomnia; infrequently - anxiety, confusion, nervousness; rarely - psychotic reactions (including hallucinations, paranoia), depression, agitation, unusual dreams, nightmares; unknown - psychotic reactions with self-destructive behavior (including suicidal thoughts or actions).
From the nervous system:
common - headache, dizziness; uncommon - drowsiness, tremor, dysgeusia; rare - convulsions, paresthesia; unknown - peripheral sensory or sensorimotor neuropathy, parosmia (including anosmia), dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension.
On the part of the organs of vision:
Rare: visual disturbances such as blurred vision; Not known: temporary loss of vision, uveitis.
On the part of the organs of hearing and balance:
infrequently - vertigo; rarely - tinnitus; unknown - hearing impairment, hearing loss.
From the heart:
Rare: tachycardia, palpitations; Not known: ventricular tachycardia (which may lead to cardiac arrest), ventricular arrhythmia such as torsade de pointes (predominantly in patients with risk factors for QT prolongation), electrocardiogram QT prolongation.
From the vascular side:
rarely - arterial hypotension.
On the part of the respiratory system:
uncommon – dyspnea; unknown – bronchospasm, allergic pneumonitis.
From the digestive tract:
often - diarrhea, vomiting, nausea; infrequently - abdominal pain, dyspepsia, flatulence, constipation; unknown - hemorrhagic diarrhea, which may indicate enterocolitis (including pseudomembranous colitis), pancreatitis.
common - increased levels of liver enzymes in the blood plasma (ALT/AST, alkaline phosphatase, GGTP); uncommon - increased levels of bilirubin in the blood plasma; unknown - jaundice and severe liver damage (including cases of acute liver failure, sometimes fatal), mainly in patients with severe underlying diseases, hepatitis.
Skin and subcutaneous tissue disorders:
infrequently - rash, itching, urticaria, hyperhidrosis; unknown - toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions, leukocytic vasculitis, stomatitis.
Musculoskeletal and connective tissue disorders:
uncommon - arthralgia, myalgia; rare - tendon disorders, including inflammation (e.g. Achilles tendon), muscle weakness, which may be of particular importance for patients with myasthenia gravis; unknown - rhabdomyolysis, tendon rupture (e.g. Achilles), ligament rupture, muscle rupture, arthritis.
From the kidneys and urinary system:
uncommon - increased plasma creatinine levels; rare - acute renal failure (e.g. due to interstitial nephritis).
General disorders:
uncommon – asthenia; rare – pyrexia; unknown – pain, including in the back, chest and extremities.
Other undesirable side effects associated with the use of fluoroquinolones include attacks of porphyria in patients with porphyria.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ºC, out of the reach of children.
Packaging
7 tablets in a blister, 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
World Medicine Ilach San. Ve Tij. A. Sh.
Location of the manufacturer and its business address
15 Temmuz Mahalleshi Cami Yolu Caddesi No. 50 Guneshli Bagcilar/Istanbul, Turkey.
