Levox-750
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOX-500, LEVOX-750 (LEVOX-500, LEVOX-750)
Composition:
Active substance: levofloxacin;
One tablet contains levofloxacin hemihydrate equivalent to 500 mg or 750 mg of anhydrous levofloxacin;
Excipients: microcrystalline cellulose, hypromellose, sodium croscarmellose, crospovidone, colloidal anhydrous silicon dioxide, purified talc, magnesium stearate, coating (Coat Color FC4S-H (White), polyethylene glycol 6000, hypromellose, titanium dioxide (E 171)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
500 mg tablets: capsule-shaped, film-coated, with a break line on one side and the imprint "500" on the other, white or almost white;
750 mg tablets: capsule-shaped, film-coated, with a break line on one side and the imprint "750" on the other, white or almost white.
Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin. ATC code J01MA12.
Pharmacological properties.
Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones,
the S-enantiomer of the racemic mixture of the drug ofloxacin.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.
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 concentration-time curve (AUC) to the minimum inhibitory concentration (MIC).
Mechanism of resistance
The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones.
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 recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from moderately susceptible (intermediate) organisms, and moderately susceptible from resistant organisms, are presented in the table below.
EUCAST clinical breakpoints for levofloxacin (20.06.2006)
| 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 |
| S. pneumoniae1 |
≤ 2 mg/L |
> 2 mg/L |
| Streptococcus A, B, C, G |
≤ 1 mg/L |
> 2 mg/L |
| H. influenzae, M. catarrhalis2 |
≤ 1 mg/L |
> 1 mg/L |
| Species-unrelated breakpoints3 |
≤ 1 mg/L |
> 2 mg/L |
| 1 The susceptible breakpoint (MIC) for S. pneumoniae has been increased from 1.0 to 2.0 mg/L to inhibit growth of wild-type strains of this organism that show variability in this parameter. The breakpoints apply to high-dose therapy. 2 Strains with MIC values above the susceptible breakpoint are very rare or have not yet been reported. Testing for identification and antimicrobial susceptibility of any such isolate should be repeated; if confirmed, the isolate should be sent to a reference laboratory. 3 Species-unrelated MIC breakpoints were defined primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the MIC distribution of specific species. These breakpoints are used only for species for which no specific breakpoint has been defined, and are not used for species where susceptibility testing is not recommended or where insufficient data are available (Enterococcus, Neisseria, gram-negative anaerobes). |
||
The recommended CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) MIC breakpoints for levofloxacin, which distinguish susceptible from intermediate organisms and intermediate from resistant organisms, are presented in the table below for MIC testing (μg/mL) or disk diffusion method (zone diameter [mm] using a 5 μg levofloxacin disk).
Recommended CLSI MIC and disk diffusion breakpoints for levofloxacin (M100-S17, 2007)
| Pathogen |
Susceptible |
Resistant |
| Enterobacteriaceae |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| Non-Enterobacteriaceae |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| Acinetobacter spp. |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| Stenotrophomonas maltophilia |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| Staphylococcus spp. |
≤ 1 µg/mL ≥ 19 mm |
≥ 4 µg/mL ≤ 15 mm |
| Enterococcus spp. |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| H. influenzae M. catarrhalis1 |
≤ 2 µg/mL ≥ 17 mm |
|
| Streptococcus pneumoniae |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| Beta-hemolytic Streptococcus |
≤ 2 µg/mL ≥ 17 mm |
≥ 8 µg/mL ≤ 13 mm |
| 1 The absence or rare occurrence of resistant strains precludes the need to define any categories other than "susceptible." For isolates yielding results that suggest the "non-susceptible" category, organism identification and antimicrobial susceptibility test results should be confirmed by a reference laboratory using the CLSI reference dilution method. |
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Antibacterial spectrum
Resistance prevalence may vary geographically and over time for selected species, so it is advisable to obtain local resistance data, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the agent at least questionable for certain types of infections.
| Commonly susceptible organisms Aerobic gram-positive bacteria Staphylococcus aureus* methicillin-sensitive, Staphylococcus saprophyticus, Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae*, Streptococcus pyogenes*. Aerobic gram-negative bacteria Burkholderia cepacia**, Eikenella corrodens, Haemophilus influenzae*, Haemophilus para-influenzae*, Klebsiella oxytoca, Klebsiella pneumoniae*, 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 for 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 agglomerans, Enterobacter cloacae*, Escherichia coli*, Morganella morganii*, Proteus mirabilis*, Providencia stuartii, Pseudomonas aeruginosa*, Serratia marcescens*. Anaerobic bacteria Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thetaiotamicron**, Bacteroides vulgatus**, Clostridium difficile**. |
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
** Natural moderate susceptibility.
Other data
Hospital-acquired infections caused by P. aeruginosa may require combination therapy.
Pharmacokinetics.
Absorption
Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) reached within 1 hour. Absolute bioavailability is approximately 100%.
Food has almost no effect on the absorption of levofloxacin.
Distribution
Approximately 30–40% of levofloxacin is protein-bound in plasma. There is virtually no accumulation of levofloxacin with repeated administration of 500 mg once daily. A slight but predictable accumulation occurs after repeated doses of 500 mg twice daily. Steady-state concentrations are achieved within 3 days.
Penetration into tissues and body fluids
Penetration into bronchial mucosa, bronchial secretions, and lung tissue (BSLT)
Maximum concentrations of levofloxacin in bronchial mucosa and bronchial secretions after a 500 mg oral dose were 8.3 µg/g and 10.8 µg/mL, respectively. These levels were achieved within 1 hour after dosing.
Penetration into lung tissue
Maximum concentration of levofloxacin in lung tissue after a 500 mg oral dose was approximately 11.3 µg/g, reached 4–6 hours after administration. Concentrations in lung tissue exceed those in plasma.
Penetration into bladder contents
Maximum concentrations of levofloxacin in bladder contents of 4.0–6.7 µg/mL were achieved 2–4 hours after dosing, following 3 days of treatment with 500 mg once or twice daily.
Penetration into cerebrospinal (CSF) fluid
Levofloxacin penetrates poorly into cerebrospinal fluid.
Penetration into prostate tissue
After 3 days of oral administration of 500 mg levofloxacin once daily, mean concentrations in prostate tissue were 8.7 µg/g, 8.2 µg/g, and 2.0 µg/g at 2, 6, and 24 hours, respectively. The mean prostate/plasma concentration ratio was 1.84.
Urine concentrations
Mean urine concentrations of levofloxacin 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.
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
After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose).
There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that oral and intravenous routes of administration are interchangeable.
Linearity
Levofloxacin exhibits linear pharmacokinetics over the range of 50–600 mg.
Patients with renal impairment
Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, renal excretion and clearance are reduced, and elimination half-life is prolonged, as shown in the table below:
| Creatinine clearance (ml/min) |
< 20 |
20-40 |
50-80 |
| Renal clearance (ml/min) |
13 |
26 |
57 |
| Elimination half-life (hours) |
35 |
27 |
9 |
Geriatric patients
There are no significant differences in the pharmacokinetics of levofloxacin between younger and elderly patients, except for differences related to creatinine clearance.
Gender differences
Separate analysis has shown minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.
Clinical characteristics.
Indications.
Levofloxacin is indicated in adults for the treatment of the following infections caused by microorganisms sensitive to levofloxacin:
- acute bacterial sinusitis;
- exacerbation of chronic bronchitis;
- community-acquired pneumonia;
- complicated and uncomplicated skin and soft tissue infections;
- nosocomial pneumonia;
- acute pyelonephritis, complicated and uncomplicated urinary tract infections;
- chronic bacterial prostatitis;
- pulmonary form of anthrax: post-exposure prophylaxis and treatment.
Levofloxacin in this pharmaceutical form (film-coated tablets) may be used to complete the course of therapy in patients who have shown clinical improvement during initial treatment with levofloxacin intravenous solution.
Official recommendations on the appropriate use of antibacterial agents should be taken into account.
Contraindications.
- Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the drug;
- epilepsy;
- tendon damage associated with the use of fluoroquinolones;
- pediatric age (under 18 years);
- pregnancy and lactation.
Interaction with other medicinal products and other forms of interaction.
Effect of other medicinal products on this medicinal product
Iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine
Absorption of levofloxacin is significantly reduced when iron salts, antacids containing magnesium or aluminium, or didanosine (only formulations of didanosine containing aluminium- or magnesium-based buffering agents) are taken concomitantly. Concomitant administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. The drug should be administered at least 2 hours before or 2 hours after taking medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine with aluminium- or magnesium-containing buffering agents (see section "Dosage and administration"). Calcium salts have minimal effect on the oral absorption of levofloxacin.
Sucralfate
The bioavailability of the drug is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to administer sucralfate 2 hours after taking the drug (see section "Dosage and administration").
Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs)
No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant lowering of the seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs, or other agents that reduce the seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered alone.
Probenecid and cimetidine
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both agents can block tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical relevance. Levofloxacin should be used with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.
Other information
Clinical pharmacology studies have demonstrated that the following medicinal products do not have a clinically significant effect on the pharmacokinetics of levofloxacin: calcium carbonate, digoxin, glyburide, ranitidine.
Effect of the drug on other medicinal products
Cyclosporine
The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.
Vitamin K antagonists
When used concomitantly with vitamin K antagonists (e.g., warfarin), an increase in coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding, including severe bleeding, has 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 relevant information
Levofloxacin does not affect the pharmacokinetics of theophylline, a substrate of the CYP1A2 enzyme, 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 regardless of food intake.
Special Warnings and Precautions for Use
The use of levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful benefit-risk assessment (see section "Contraindications").
Prolonged, disabling and potentially irreversible serious adverse reactions
In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems—sometimes multiple—(musculoskeletal, nervous system, psychiatric, and sensory organs) have been reported, regardless of age or underlying risk factors.
Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction. Patients should be advised to seek immediate medical consultation.
The use of levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and only after careful benefit-risk assessment.
MRSA (Methicillin-resistant Staphylococcus aureus)
There is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing confirms 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 properly diagnosed.
Resistance to fluoroquinolones in Escherichia coli (the most common cause of urinary tract infections) varies across countries. Local prevalence of fluoroquinolone resistance in E. coli should be taken into account when prescribing fluoroquinolones.
Pulmonary anthrax
The use of levofloxacin for treatment in humans is based on in vitro data showing susceptibility of Bacillus anthracis, experimental animal data, and limited human experience. Physicians should refer to national and/or international guidelines on the treatment of anthrax.
Tendinitis and tendon rupture
Tendinitis may rarely occur. This most commonly affects the Achilles tendon (sometimes bilaterally), but is not limited to it, and may involve tendon rupture and tenosynovitis. This adverse effect may occur within 48 hours of starting treatment with quinolones or fluoroquinolones and has been observed even several months after discontinuation of therapy; it may also be bilateral. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients undergoing solid organ transplantation, patients receiving levofloxacin at a dose of 1000 mg per day, and patients taking corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. Dose adjustment in elderly patients should be based on creatinine clearance (see section "Dosage and Administration"). Close monitoring of such patients is necessary when levofloxacin is prescribed. Patients should consult their physician if they experience symptoms of tendinitis (e.g., pain, swelling, inflammation). If tendinitis is suspected, levofloxacin should be discontinued immediately and alternative treatment initiated (e.g., immobilization) for the affected tendon or limb (see sections "Contraindications" and "Adverse Reactions"). Corticosteroids should not be used if signs of tendinopathy occur.
Clostridium difficile-associated disease
Diarrhea, especially severe, persistent, or hemorrhagic diarrhea occurring during or after treatment (including several weeks after therapy), may be symptoms of Clostridium difficile-associated disease. The most severe form of this condition is pseudomembranous colitis (see section "Adverse Reactions"). Therefore, physicians should consider the possibility of C. difficile-associated disease in patients who develop severe diarrhea during or after treatment with levofloxacin. If C. difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated urgently. Antiperistaltic medicinal products are contraindicated in this clinical situation.
Patients predisposed to seizures
Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures, such as those with prior central nervous system disorders, concomitant therapy with fenbufen or similar NSAIDs, or other drugs that increase seizure susceptibility (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 known deficiency in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions when treated with quinolone-class antibacterial agents. Therefore, if levofloxacin must be used, such patients should be monitored for possible hemolysis.
Patients with renal impairment
Since levofloxacin is primarily excreted via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and Administration").
Hypersensitivity reactions
Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock), including after administration of the initial dose (see section "Adverse Reactions"). In such cases, patients should discontinue the drug immediately, seek medical advice, and initiate appropriate treatment.
Severe skin adverse reactions
Severe cutaneous adverse reactions (SCAR), including toxic epidermal necrolysis (also known as Lyell’s syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported. These reactions may be life-threatening or fatal (see section "Adverse Reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If such signs or symptoms appear, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS during levofloxacin treatment, re-administration of levofloxacin is absolutely contraindicated. Patients should be advised to seek immediate medical attention if skin or mucosal reactions occur.
Alterations in blood glucose levels
As with all quinolones, cases of blood glucose disturbances, including both hypoglycemia and hyperglycemia, have been reported, typically in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been documented. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse Reactions").
If a patient reports disturbances in blood glucose levels, treatment should be discontinued immediately and alternative antibacterial therapy without fluoroquinolones considered.
Prevention of photosensitization
Cases of photosensitization have been reported during levofloxacin therapy (see section "Adverse Reactions"). To avoid this, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) during and for 48 hours after discontinuation of levofloxacin.
Patients receiving vitamin K antagonists
Due to the potential for increased coagulation test results (prothrombin time/international normalized ratio) and/or increased risk of hemorrhagic complications in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these drugs are used together (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 rare cases, these progressed to suicidal ideation 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 QT prolongation 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 conditions (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Dosage and Administration" ("Elderly patients"), "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Overdose").
Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used cautiously in these patient groups.
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones. Levofloxacin should be discontinued if patients experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness to prevent irreversible damage.
Hepatobiliary disorders
Cases of hepatic necrosis up to fatal liver failure have been reported during levofloxacin use, 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 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 post-marketing experience, 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.
Visual disturbances
If any visual disturbances or ocular adverse reactions occur during levofloxacin therapy, patients should seek immediate ophthalmological consultation (see sections "Adverse Reactions" and "Effect on Ability to Drive and Use Machines").
Superinfection
The use of levofloxacin, especially prolonged use, may lead to overgrowth of organisms resistant to the drug. If superinfection develops during therapy, appropriate measures should be taken.
Effect on laboratory test results
In patients taking levofloxacin, urine opiate screening may yield false-positive results. Positive opiate screening results should be confirmed using more specific methods.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.
Official guidelines on the appropriate use of antibacterial agents should be considered.
Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency
Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal), and regurgitation/functional insufficiency of any cardiac valve have been reported in patients taking fluoroquinolones (see section "Adverse Reactions").
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with existing diagnoses 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, arterial hypertension, rheumatoid arthritis); or additionally
- for aortic aneurysm/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 sudden abdominal, chest, or back pain occurs.
Patients should be advised to seek immediate medical help if acute shortness of breath, new palpitations, or development of abdominal or lower limb edema occurs.
Important information on excipients
This film-coated tablet formulation containing 500 mg levofloxacin contains 33.0 mg of sodium; the 750 mg tablet contains 50.0 mg of sodium.
Caution is advised when administering to patients on a sodium-restricted diet.
Use during pregnancy or breastfeeding
Pregnancy
Data on the use of levofloxacin in pregnant women are limited.
Animal studies do not indicate direct or indirect harmful effects with regard to reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of cartilage damage in the growing organism from fluoroquinolones, levofloxacin should not be administered to pregnant women.
If pregnancy is diagnosed during treatment, this should be reported to the physician.
Breastfeeding
Levofloxacin is contraindicated in breastfeeding women. Information on the passage of levofloxacin into breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolone-induced cartilage damage in the growing organism, levofloxacin should not be administered to breastfeeding women.
Fertility
Levofloxacin does not cause impairment of fertility or reproductive function in animals.
Effect on Ability to Drive and Use Machines
Patients who operate vehicles or machinery should be aware of possible adverse effects on the nervous system (dizziness/vertigo, somnolence, confusion, visual and auditory disturbances, motor disturbances including gait disturbances), which may impair concentration and reaction speed, thereby increasing the risk in situations where these abilities are critical (e.g., driving or operating machinery).
Dosage and Administration
The drug is taken once daily. The dosage 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 body temperature normalization or until microbiological tests confirm eradication of the causative pathogens.
Levofloxacin tablets may be used to complete the treatment course in patients who have shown improvement during initial therapy with levofloxacin in intravenous form, using the same dosage regimen.
Tablets should be swallowed whole with sufficient fluid. The required dose may be achieved by dividing the tablet along the score line. The drug may be taken independently 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 didanosine formulations containing buffering agents of aluminum or magnesium), and sucralfate, as reduced absorption may occur (see section "Interaction with other medicinal products and other forms of interaction").
Recommended dosage Ufor adult patients with normal renal function U*, in whom creatinine clearance is over 50 mL/min*
| Indications |
Daily dose |
Duration of treatment |
| Nosocomial pneumonia |
750 mg |
7–14 days |
| Community-acquired pneumonia |
500 mg |
7–14 days |
| 750 mg |
5 days |
|
| Complicated skin and soft tissue infections |
750 mg |
7–14 days |
| Uncomplicated skin and soft tissue infections |
500 mg |
7–10 days |
| Chronic bacterial prostatitis |
500 mg |
28 days |
| Pulmonary form of anthrax |
500 mg |
8 weeks |
| Complicated urinary tract infections including pyelonephritis |
250 mg |
10 days |
| 750 mg |
5 days |
|
| Uncomplicated urinary tract infections |
250 mg |
3 days |
| Acute bacterial exacerbation of chronic bronchitis |
500 mg |
7 days |
| Acute bacterial sinusitis |
500 mg |
10–14 days |
| 750 mg |
5 days |
Dosing for patients with renal impairment in whom creatinine clearance
is less than 50 ml/min
| Creatinine clearance over 50 ml/min |
Creatinine clearance 20 - 49 ml/min |
Creatinine clearance 10 - 19 ml/min |
Hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) |
| 750 mg every 24 hours |
750 mg every 48 hours |
750 mg – initial dose, then 500 mg every 48 hours |
750 mg – initial dose, then 500 mg every 48 hours |
| 500 mg every 24 hours |
500 mg – initial dose, then 250 mg every 24 hours |
500 mg – initial dose, then 250 mg every 48 hours |
500 mg – initial dose, then 250 mg every 48 hours |
| 250 mg every 24 hours |
No dose adjustment required |
250 mg every 48 hours. For treatment of uncomplicated urinary tract infections, no dose adjustment required |
No information on dose adjustment available. |
Dosing in patients with hepatic impairment. Dose adjustment is not required, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.
Dosing in elderly patients. If renal function is not impaired, dose adjustment is not necessary (see section "Special precautions" ("Tendinitis and tendon rupture", "QT interval prolongation")).
Children.
Levofloxacin is contraindicated in children and adolescents (under 18 years of age), as damage to joint cartilage cannot be excluded.
Overdose.
Symptoms
The most significant expected symptoms of overdose involve the central nervous system (confusion, dizziness, disturbances of consciousness and seizures, hallucinations, tremor); gastrointestinal reactions such as nausea and erosion of mucous membranes. According to study results, administration of doses higher than therapeutic ones was associated with QT interval prolongation.
Treatment
Treatment is symptomatic. In cases of overdose, careful monitoring of the patient, including ECG, is required.
In acute overdose, gastric lavage should be performed. Antacid agents are used to protect gastric mucosa.
Hemodialysis, including peritoneal dialysis or continuous arteriovenous hemofiltration (CAVH), is not effective for removing levofloxacin from the body. There are no specific antidotes.
Adverse reactions.
The adverse reactions listed below are categorized by organ systems and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, ≤ 1/100), rare (≥ 1/10000, ≤ 1/1000), frequency not known (cannot be estimated from the available data).
Within each frequency group, adverse reactions are listed in order of decreasing severity.
| System Organ Classes |
Common |
Uncommon |
Rare |
Frequency not known |
| Infections and infestations |
Fungal infections, including infections caused by Candida species; resistance of pathogenic microorganisms |
|||
| Blood and lymphatic system disorders |
Leukopenia, eosinophilia |
Thrombocytopenia, neutropenia |
Pancytopenia, agranulocytosis, hemolytic anemia |
|
| Immune system disorders |
Angioneurotic edema, hypersensitivity (see section "Special warnings and precautions for use") |
Anaphylactic/anaphylactoid shock (see section "Special warnings and precautions for use") |
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| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
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| Metabolism and nutrition disorders |
Anorexia |
Hypoglycemia, mainly in diabetic patients (see section "Special warnings and precautions for use") |
Hypoglycemic coma, hyperglycemia (see section "Special warnings and precautions for use") |
|
| Psychiatric disorders* |
Insomnia |
Anxiety, confusion, nervousness |
Psychotic reactions (e.g., with hallucinations, paranoia); depression, agitation, sleep disorders, nightmares, delirium |
Psychotic reactions with self-harming behavior, including suicidal ideation or actions (see section "Special warnings and precautions for use") |
| Nervous system disorders* |
Headache, dizziness |
Somnolence, tremor, dysgeusia (subjective taste disturbance) |
Seizures (see sections "Contraindications" and "Special warnings and precautions for use"), paraesthesia |
Peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), smell disorders (parosmia), including anosmia (loss of smell), dyskinesia (impaired motor coordination), extrapyramidal disorders, ageusia, syncope (fainting); benign intracranial hypertension |
| Eye disorders* |
Visual disturbances such as blurred vision, unclear vision (see section "Special warnings and precautions for use") |
Transient loss of vision (see section "Special warnings and precautions for use") |
||
| Ear and labyrinth disorders* |
Vertigo |
Tinnitus |
Hearing loss, impaired hearing |
|
| Cardiac disorders** |
Tachycardia, palpitations |
Ventricular tachycardia, which may lead to cardiac arrest Ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG (see sections "Special warnings and precautions for use" ("QT interval prolongation") and "Overdose") |
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| Vascular disorders** |
Arterial hypotension |
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| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
Bronchospasm, allergic pneumonitis |
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| Gastrointestinal disorders |
Diarrhea, vomiting, nausea |
Abdominal pain, dyspepsia, flatulence, constipation |
Hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis |
|
| Hepatobiliary disorders |
Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT) |
Elevated blood bilirubin levels |
Jaundice and severe liver injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use"), hepatitis |
|
| Skin and subcutaneous tissue disorders |
Rash, pruritus, urticaria, hyperhidrosis |
Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), fixed drug eruption |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis |
|
| Musculoskeletal and connective tissue disorders* |
Arthralgia, myalgia |
Tendon disorders (see section "Special warnings and precautions for use"), including tendon inflammation (tendinitis) (e.g., Achilles tendon). Muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special warnings and precautions for use") |
Rhabdomyolysis, tendon rupture (e.g., Achilles tendon, see section "Special warnings and precautions for use"), ligament rupture, muscle rupture, arthritis |
|
| Renal and urinary disorders |
Elevated blood creatinine levels |
Acute renal failure (e.g., due to interstitial nephritis) |
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| General disorders and administration site conditions* |
Asthenia |
Increased body temperature (pyrexia) |
Pain (including back, chest, limb pain) |
aAnaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.
bSkin and mucous membrane reactions may sometimes occur even after administration of the first dose.
*Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, organ system classes and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance; in some cases, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell) have been associated with the use of quinolones and fluoroquinolones, regardless of pre-existing risk factors (see section "Special precautions").
**Aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Special precautions").
Other adverse reactions associated with fluoroquinolone use include porphyria attacks in patients with porphyria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging.
Film-coated tablets, 500 mg or 750 mg, 10 film-coated tablets per blister, 1 blister per cardboard pack.
Prescription status. Prescription only.
Manufacturer.
Tulip Lab Pvt. Ltd., India/Tulip Lab Pvt. Ltd., India.
Manufacturer's address and location of manufacturing operations.
F-20/21, Ranjangaon MIDC, Tal. Shirur, Dist – Pune, India.
F-20/21, Ranjangaon MIDC, Tal. Shirur, Dist – Pune, India.
Marketing Authorization Holder.
Tulip Lab Private Limited, India/Tulip Lab Private Limited, India.
Address of the Marketing Authorization Holder.
4024, A-Wing, Oberoi Garden Estate, Chandivali, Andheri (East), Mumbai – 400072, India.
4024, A-Wing, Oberoi Garden Estate, Chandivali, Andheri (East), Mumbai – 400072, India.