Levofloxacin
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN (LEVOFLOXACIN)
Composition:
Active substance: 1 tablet contains 256.23 mg of levofloxacin hemihydrate, equivalent to 250 mg of levofloxacin;
1 tablet contains 512.46 mg of levofloxacin hemihydrate, equivalent to 500 mg of levofloxacin;
Excipients: hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate, polyethylene glycol 6000, talc, iron oxide red (E 172), iron oxide yellow (E 172), titanium dioxide (E 171).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: round-shaped film-coated tablets, light pink to light brown in color with a pinkish hue, with convex upper and lower surfaces.
On cross-section, under magnification, a core of light yellow or yellowish-white color surrounded by a single continuous layer is visible.
Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. Levofloxacin.
ATC code J01MA12.
Pharmacological properties.
Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent from the fluoroquinolone group and 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 gyrase and topoisomerase IV complex.
Pharmacokinetic/pharmacodynamic relationship. The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic curve (AUC) to the minimum inhibitory (inhibitory) concentration (MIC).
Mechanism of resistance. Resistance to levofloxacin develops through a stepwise process due to mutations in the target site of both type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as impermeable barrier (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.
Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.
Clinical breakpoints. The clinical breakpoints for levofloxacin MIC recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility and microorganisms with intermediate susceptibility from resistant ones, are presented in the table below for MIC testing (mg/L).
EUCAST clinical breakpoints for levofloxacin (version 2.0, 2012-01-01):
| Pathogen |
Susceptible |
Resistant |
| Enterobacteriaceae |
≤ 1 mg/l |
>2 mg/l |
| Pseudomonas spp. |
≤ 1 mg/l |
>2 mg/l |
| Acinetobacter spp. |
≤ 1 mg/l |
>2 mg/l |
| Staphylococcus spp. |
≤ 1 mg/l |
>2 mg/l |
| Streptococcus pneumoniae 1 |
≤ 2 mg/l |
>2 mg/l |
| Streptococcus A, B, C, G |
≤ 1 mg/l |
>2 mg/l |
| Haemophilus influenzae 2, 3 |
≤ 1 mg/l |
>1 mg/l |
| Moraxella catarrhalis 3 |
≤ 1 mg/l |
>1 mg/l |
| Non-species related breakpoints 4 |
≤ 1 mg/l |
>2 mg/l |
|
||
Antibacterial spectrum. The prevalence of resistance may vary geographically and over time for selected species; local information on resistance should be sought, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence is such that the utility of the agent is at least questionable for certain types of infections.
| Commonly susceptible species |
| Aerobic gram-positive bacteria Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes. |
| Aerobic gram-negative bacteria Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri. |
| Anaerobic bacteria Peptostreptococcus |
| Others Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum. |
| Species in which acquired (secondary) resistance may be problematic |
| Aerobic gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Staphylococcus coagulase spp. |
| Aerobic gram-negative bacteria Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens. |
| Anaerobic bacteria Bacteroides fragilis |
| Naturally resistant strains Aerobic gram-positive bacteria Enterococcus faecium |
*Methicillin-resistant Staphylococcus aureus is highly likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.
Pharmacokinetics.
Absorption.
Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) achieved within 1 hour. Absolute bioavailability is approximately 100%.
Food has almost no effect on the absorption of levofloxacin.
Steady-state concentrations are reached within 48 hours with a dosing regimen of 500 mg once or twice daily.
Distribution.
Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating good tissue penetration throughout the body.
Penetration into tissues and body fluids.
Levofloxacin penetrates well into bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. Levofloxacin penetrates poorly into cerebrospinal fluid.
Biotransformation.
Levofloxacin undergoes minimal metabolism. The metabolites are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination.
Following both oral and intravenous administration, levofloxacin is slowly eliminated from plasma (elimination half-life is 6–8 hours). Total clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin between intravenous and oral administration, indicating interchangeability of these routes.
Linearity.
Levofloxacin exhibits linear pharmacokinetics over the range of 50–1000 mg.
Patients with renal impairment.
Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, renal excretion and creatinine clearance are reduced, and elimination half-life is prolonged, as shown in the table below:
Pharmacokinetics in renal impairment after a single 500 mg oral dose.
| Creatinine clearance (mL/min) |
< 20 |
20–49 |
50–80 |
| Renal clearance (mL/min) |
13 |
26 |
57 |
| Half-life (hours) |
35 |
27 |
9 |
Geriatric patients.
There are no significant differences in the pharmacokinetics of levofloxacin in younger and elderly patients, except for differences related to creatinine clearance.
Gender differences.
Separate analysis in male and female patients demonstrated minor differences in levofloxacin pharmacokinetics depending on gender. There is no evidence that these gender differences are clinically significant.
Clinical characteristics.
Indications.
Levofloxacin is indicated for the treatment in adults of infections caused by microorganisms sensitive to levofloxacin:
- Acute bacterial sinusitis;
- Exacerbations of chronic obstructive pulmonary disease, including bronchitis;
- Community-acquired pneumonia;
- Complicated skin and soft tissue infections;
- Uncomplicated cystitis.
This medicinal product should be used only when other antibacterial agents typically prescribed for initial treatment of these infections cannot be used.
- Complicated urinary tract infections (including acute pyelonephritis);
- Chronic bacterial prostatitis;
- Pulmonary form of anthrax: post-exposure prophylaxis and treatment.
This oral formulation of levofloxacin may be used to complete a course of therapy in patients who have shown clinical improvement during initial treatment with intravenous levofloxacin.
Official recommendations on the appropriate use of antibacterial agents should be taken into account.
Contraindications.
- Hypersensitivity to levofloxacin, other fluoroquinolones, or to any of the excipients of the medicinal product;
- Epilepsy;
- Tendon disorders related to the use of fluoroquinolones;
- Paediatric age (under 18 years);
- Pregnancy and breastfeeding.
Interaction with other medicinal products and other forms of interaction.
Effects of other medicinal products on levofloxacin.
Iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine.
Absorption of levofloxacin is significantly reduced when iron salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal formulations of didanosine containing aluminium- or magnesium-based buffering agents) are administered concomitantly with the drug. Concurrent administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. Medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal formulations of didanosine containing aluminium- or magnesium-based buffering agents) should not be administered within 2 hours before or after the intake of this drug (see section "Dosage and administration"). Calcium salts have minimal effect on the oral absorption of levofloxacin.
Sucralfate.
The bioavailability of levofloxacin tablets is significantly reduced when administered concomitantly with sucralfate. If a patient needs to take both sucralfate and levofloxacin, it is preferable to administer sucralfate at least 2 hours after taking the drug (see section "Dosage and administration").
Theophylline, fenbufen, or similar non-steroidal anti-inflammatory drugs (NSAIDs).
No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when fluoroquinolones are used concomitantly with theophylline, NSAIDs, or other agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.
Probenecid and cimetidine.
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% with cimetidine and by 34% with probenecid. This is because both drugs can block the tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that these statistically significant kinetic differences would have clinical relevance. Caution should be exercised when administering levofloxacin concomitantly with drugs affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.
Other information.
The following medicinal products have no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly: calcium carbonate, digoxin, glyburide (glibenclamide), ranitidine.
Effects of levofloxacin on other medicinal products.
Cyclosporine.
The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.
Vitamin K antagonists.
When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (prothrombin time/international normalized ratio) and/or bleeding events, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (see section "Special precautions for use").
MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL.
Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic agents) (see section "Special precautions for use" ("QT interval prolongation")).
Other significant information.
No effect of levofloxacin on the pharmacokinetics of theophylline (a substrate of CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.
Other forms of interaction. Food intake.
No clinically significant interaction with food has been observed; therefore, the drug can be taken independently of food intake.
Special precautions for use.
Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or products containing fluoroquinolones (see section "Adverse reactions"). Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful benefit/risk assessment (see section "Contraindications").
The benefits of treatment with levofloxacin, particularly in mild infections, should be evaluated considering the information provided in this section.
Prolonged, disabling and potentially irreversible serious adverse reactions.
Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various systems of the body—sometimes multiple systems simultaneously (including musculoskeletal, nervous, psychiatric, and sensory organs)—have been reported. The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.
MRSA (Methicillin-resistant S. aureus).
There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.
Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis, provided these infections have been appropriately diagnosed.
Resistance to fluoroquinolones in E. coli (the most common causative agent of urinary tract infections) varies across different countries. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.
Pulmonary anthrax.
The use of the drug for treatment in humans is based on in vitro susceptibility data for Bacillus anthracis, experimental animal data, and limited human experience. Physicians should refer to national and/or international established guidelines for the treatment of anthrax.
Tendinitis and tendon rupture.
Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported even 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 impaired renal function, patients who have undergone solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.
If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment with the drug should be discontinued and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.
Myoclonus.
Cases of myoclonus have been reported in patients treated with levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the dose of levofloxacin is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment initiated.
Clostridium difficile-associated disease.
Diarrhea, particularly severe, persistent, and/or with blood, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The most severe form of this disease is pseudomembranous colitis (see section "Adverse reactions"). Therefore, physicians should consider the possibility of Clostridium difficile-associated disease in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated urgently. Medicinal products that inhibit intestinal peristalsis are contraindicated in this case.
Patients with predisposition to seizures.
Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications") and, like other quinolones, should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant medications that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs (see section "Adverse reactions"), levofloxacin should be discontinued.
Patients with glucose-6-phosphate dehydrogenase deficiency.
Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis is recommended.
Patients with renal impairment.
Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required for patients with impaired renal function (renal insufficiency) (see section "Method of administration and dosage").
Hypersensitivity reactions.
Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., from angioedema to anaphylactic shock), sometimes after administration of the first dose only. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.
Severe skin adverse reactions.
Severe skin adverse reactions (SCARs), including toxic epidermal necrolysis (TEN; also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with levofloxacin (see section "Adverse reactions"). At the time of prescribing, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, treatment with levofloxacin should be discontinued immediately and alternative therapy considered. If a patient has experienced a serious reaction such as SJS, TEN, or DRESS with levofloxacin, re-treatment with levofloxacin in this patient is absolutely contraindicated.
Alterations in blood glucose levels.
As with all quinolones, cases of blood glucose disturbances—including both hypoglycemia and hyperglycemia—have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section "Adverse reactions").
Prevention of photosensitization.
Cases of photosensitization have been reported during treatment with levofloxacin (see section "Adverse reactions"). To prevent photosensitization, patients should be advised to avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., sunlamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.
Patients receiving vitamin K antagonists.
Due to the possible increase in coagulation parameters (prothrombin time/international normalized ratio) and/or increased frequency of hemorrhagic complications in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").
Psychotic reactions.
Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.
QT interval prolongation.
Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:
- congenital or acquired long QT syndrome;
- concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
- electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
- cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Method of administration and dosage (Elderly patients)", "Interaction with other medicinal products and other forms of interaction", "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 patient groups.
Peripheral neuropathy.
Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients treated with quinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician immediately to prevent progression to potentially irreversible conditions.
Hepatobiliary disorders.
Cases of hepatic necrosis up to hepatic failure with fatal outcome have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Exacerbation of myasthenia gravis.
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions including fatalities and cases requiring respiratory support have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.
Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency.
Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and of regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").
Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with an existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:
- for both aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis), or additionally
- for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or additionally
- for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection, and rupture may be increased in patients receiving systemic corticosteroids concomitantly.
Patients should seek immediate medical attention in emergency departments if they experience sudden abdominal, chest, or back pain.
Patients should be advised to seek immediate medical help if they experience acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema.
Visual disturbances.
If any visual disturbances or ocular adverse reactions occur during levofloxacin treatment, patients should consult an ophthalmologist immediately (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse reactions").
Superinfection.
The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms not susceptible (resistant) to the drug. If superinfection develops during therapy, appropriate measures should be taken.
Effect on laboratory test results.
In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate screening results by more specific methods may be necessary.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, thereby leading to false-negative results in bacteriological diagnosis of tuberculosis.
Official guidelines on the appropriate use of antibacterial agents should be taken into account.
Blood disorders.
During treatment with levofloxacin, bone marrow dysfunction may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse reactions"). If any of these disorders are suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.
Use during pregnancy or breastfeeding.
Due to the lack of studies and the potential for quinolones to damage cartilage in the growing organism, the drug is contraindicated in pregnant and breastfeeding women. If pregnancy is diagnosed during treatment, this should be reported to the physician.
Levofloxacin did not cause impairment of fertility or reproductive function in rats.
Ability to influence reaction speed when driving or operating machinery.
Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient’s ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).
Method of administration and dosage.
Levofloxacin tablets are taken 1–2 times a day. The dose depends on the type, severity of infection, and susceptibility of the likely causative agent.
The duration of treatment depends on the course of the disease and should not exceed 14 days. It is recommended to continue administration of the drug for at least 48–72 hours after normalization of body temperature or confirmed microbiological eradication of the pathogen.
Levofloxacin tablets should be swallowed whole, without chewing, with an adequate amount of liquid. Tablets may be taken regardless of food intake.
The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for formulations containing aluminum or magnesium in buffering agents), and sucralfate (see section "Interaction with other medicinal products and other forms of interaction").
Tablets may be used to complete the treatment course in patients who have shown improvement during initial therapy with levofloxacin in the form of infusion solution, using the same dosage regimen.
Table 1
Recommended dosage for adult patients with normal renal function and creatinine clearance greater than 50 ml/min
| Indications |
Daily dose (depending on severity), mg |
Number of doses per day |
Treatment duration (depending on severity) |
| Acute bacterial sinusitis |
500 |
1 |
10–14 days |
| Exacerbation of chronic obstructive pulmonary disease, including bronchitis |
500 |
1 |
7–10 days |
| Community-acquired pneumonia |
500 |
1–2 |
7–14 days |
| Acute pyelonephritis |
500 |
1 |
7–10 days |
| Complicated urinary tract infections including pyelonephritis |
500 |
1 |
7–14 days |
| Uncomplicated cystitis |
250 |
1 |
3 days |
| Chronic bacterial prostatitis |
500 |
1 |
28 days |
| Complicated skin and soft tissue infections |
500 |
1–2 |
7–14 days |
| Pulmonary form of anthrax |
500 |
1 |
8 weeks |
Special populations
Table 2
Dosing for patients with renal impairment with creatinine clearance ≤ 50 ml/min.
| Dosing regimen (depending on severity of infection and nosological form) |
|||
| 250 mg/24 hours |
500 mg/24 hours |
500 mg/12 hours |
|
| Creatinine clearance |
initial dose – 250 mg |
initial dose – 500 mg |
initial dose – 500 mg |
| 50–20 mL/min |
subsequent – |
subsequent – |
subsequent – |
| 19–10 mL/min |
subsequent – |
subsequent – |
subsequent – |
| <10 mL/min (also during hemodialysis and CRRT1) |
subsequent – |
subsequent – |
subsequent – |
1 After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.
Dosage in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.
Dosage in elderly patients. If renal function is not impaired, dose adjustment is not required (see section "Special precautions").
Children.
The use of the drug is contraindicated in children and adolescents (under 18 years of age) due to the potential risk of damage to joint cartilage.
Overdose.
According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic ones, the most important signs expected after acute overdose of levofloxacin are symptoms related to the central nervous system, such as confusion, dizziness, altered consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.
During post-marketing use of levofloxacin, central nervous system effects have been observed, including confusion, myoclonus, seizures, hallucinations, and tremor.
In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Antacids may be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.
Side effects
Infections and infestations: fungal infections, including Candida species, overgrowth of other resistant microorganisms, disruption of normal intestinal flora, and development of secondary infections.
Blood and lymphatic system disorders: frequency unknown (cannot be estimated from available data): bone marrow suppression, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia; leukopenia, eosinophilia, neutropenia, thrombocytopenia, which may lead to increased susceptibility to hemorrhage or bleeding.
Immune system disorders: hypersensitivity reactions, including anaphylactic/anaphylactoid shock\1, which may occur even after the first dose within minutes or hours of administration (see section "Special precautions for use"); angioedema, urticaria, bronchospasm, dyspnea, skin and mucous membrane swelling, sudden drop in blood pressure, shock.
Metabolism and nutrition disorders: anorexia, loss of appetite, hypoglycemia, especially in patients with diabetes (see section "Special precautions for use"), hyperglycemia, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, excessive sweating, and limb tremors.
Nervous system disorders*: headache, dizziness, confusion, numbness, sleep disorders, somnolence, paresthesia, tremor, dysgeusia (subjective taste disturbance), seizures, convulsions, peripheral sensory or sensorimotor neuropathy, reduced sense of touch; olfactory disturbances (parosmia), including anosmia (loss of smell); extrapyramidal disorders, dyskinesia (impaired movement coordination), syncope (fainting), benign intracranial hypertension, taste disturbances, loss of taste (ageusia), myoclonus.
Psychiatric disorders*: insomnia, unusual dreams, nightmares, agitation, nervousness, restlessness, fear, anxiety, anxiety states, fear states, psychotic disorders (including hallucinations, paranoia), depression, anxiety, restlessness, fear states, psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions for use"), mania.
Eye disorders*: visual disturbances, blurred vision, visual blurring, transient vision loss.
Ear and labyrinth disorders*: vertigo, tinnitus, ringing in the ears, hearing impairment, hearing loss.
Cardiac disorders**: tachycardia, palpitations, ventricular arrhythmia, ventricular tachycardia, and polymorphic ventricular tachycardia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), which may lead to cardiac arrest, QT interval prolongation on electrocardiogram (see sections "Special precautions for use" (QT interval prolongation) and "Overdose").
Vascular disorders**: arterial hypotension; shock-like collapse; allergic vasculitis.
Respiratory system disorders: dyspnea, bronchospasm, allergic pneumonitis.
Gastrointestinal disorders: loss of appetite, diarrhea, nausea, vomiting, abdominal pain, dyspepsia, digestive disorders, bloating, constipation, hemorrhagic diarrhea which may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions for use"), pancreatitis, flatulence.
Hepatobiliary and biliary tract disorders: elevated liver enzyme levels (ALT/AST, alkaline phosphatase, gamma-glutamyltransferase), elevated bilirubin, hepatitis, jaundice, severe liver injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special precautions for use").
Skin and subcutaneous tissue disorders\2: skin redness, blistering, rash, pruritus, urticaria, hyperhidrosis, erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, photosensitivity reactions, increased sensitivity to sunlight and ultraviolet radiation, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.
Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions for use"), localized skin rashes caused by drugs.
Musculoskeletal and connective tissue disorders*: arthralgia, myalgia, tendon disorders (see section "Special precautions for use"), including tendon inflammation (tendinitis) (e.g., Achilles tendon), muscle weakness, which may be particularly significant in patients with severe myasthenia gravis (see section "Special precautions for use"), rhabdomyolysis, ligament rupture, muscle rupture, tendon rupture (e.g., Achilles tendon) (see section "Special precautions for use"), arthritis, joint pain, muscle pain.
Renal and urinary system disorders: elevated serum creatinine levels, acute renal failure (e.g., due to interstitial nephritis).
Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), cases of hypoglycemic coma.
General disorders*: asthenia, general weakness, fever (pyrexia), pain (including back, chest, and limb pain). As with other fluoroquinolones, porphyria attacks may occur in patients with existing porphyria.
1Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose of the drug.
2Skin and mucous membrane reactions may sometimes occur even after the first dose of the drug.
* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, body systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances).
** In patients receiving fluoroquinolones, cases of aneurysms and dissections of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported (see section "Special precautions for use").
Shelf life. 3 years.
Storage conditions.
Store at a temperature not exceeding 30°C. Keep out of reach of children.
Packaging.
10 tablets in a blister; 1 blister per cardboard box.
Prescription category. Prescription only.
Manufacturer.
PJSC "Tekhnolog".
Manufacturer's address and location of business activity.
8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.