Levflocad
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEFLOCAD (LEFLOCAD)
Composition:
Active substance: levofloxacin;
1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin 250 mg or 500 mg;
Excipients: microcrystalline cellulose, crospovidone, hydroxypropylmethylcellulose, talc, magnesium stearate;
Coating Opadry Pink 03B84851: hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 400, talc, yellow iron oxide (E 172), red iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
250 mg tablets: capsule-shaped, film-coated tablets, light beige to light pink in color, with a break line on both sides, embossed with "J" on one side and "250" on the other side of the break line, smooth on the reverse side;
500 mg tablets: capsule-shaped, film-coated tablets, light beige to light pink in color, with a break line on both sides, embossed with "J" on one side and "500" on the other side of the break line, smooth on the reverse side.
Pharmacotherapeutic group.
Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin.
ATC code J01M A12.
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. As a fluoroquinolone-class antibacterial agent, levofloxacin acts on the DNA-DNA gyrase and topoisomerase IV complex.
The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum concentration in blood serum (Cmax) or the area under the concentration-time curve (AUC) to the minimum inhibitory (suppressive) concentration (MIC (MBC)).
Resistance to levofloxacin develops through a stepwise process due to mutations in the target site in 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 sensitivity to levofloxacin.
Cross-resistance has been observed between levofloxacin and other fluoroquinolones.
Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not expected.
The recommended breakpoints for MIC values of levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which differentiate susceptible microorganisms from moderately susceptible (intermediately resistant) organisms, and moderately susceptible from resistant organisms, are presented in Table 1 of MIC testing (mg/L).
Table 1
EUCAST clinical MIC 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 pneumoniae1 |
≤2 mg/L |
>2 mg/L |
| Streptococcus A, B, C, G |
≤1 mg/L |
>2 mg/L |
| Haemophilus influenzae2,3 |
≤1 mg/L |
>1 mg/L |
| Moraxella catarrhalis3 |
≤1 mg/L |
>1 mg/L |
| Species-unrelated breakpoints4 |
≤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 obtained, 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 species Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-sensitive, Staphylococcus saprophyticus, Streptococci groups 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 where acquired resistance may be a problem Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp. Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens. Anaerobic bacteria: Bacteroides fragilis. Naturally resistant strains Aerobic gram-positive bacteria: Enterococcus faecium. |
*Methicillin-resistant S. 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 reached within 1–2 hours. Absolute bioavailability is approximately 99–100%.
Food has minimal effect on the absorption of levofloxacin.
Steady-state concentrations are achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.
Distribution
Approximately 30–40% of levofloxacin is bound to plasma proteins. The mean volume of distribution of levofloxacin is approximately 100 L after both single and repeated 500 mg doses, indicating good tissue penetration throughout the body.
Penetration into body tissues and fluids
Levofloxacin has been shown to penetrate into bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (vesicle fluid), prostate tissue, and urine. Levofloxacin penetrates poorly into cerebrospinal fluid.
Metabolism
Levofloxacin undergoes minimal metabolism, with metabolites being 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).
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 after intravenous and oral administration, indicating that these routes (oral and intravenous) are interchangeable.
Linearity
Levofloxacin follows linear pharmacokinetics over the range of 50–1000 mg.
Special populations
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.
Pharmacokinetics in renal impairment after a single 500 mg oral dose.
Table 2
| Creatinine clearance (mL/min) |
< 20 |
20–49 |
50–80 |
| Renal clearance (mL/min) |
13 |
26 |
57 |
| Elimination half-life (hours) |
35 |
27 |
9 |
Elderly patients
There are no significant differences in the pharmacokinetics of levofloxacin in younger patients and elderly patients, except for differences related to creatinine clearance.
Gender differences
Separate analysis of male and female patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.
Clinical characteristics.
Indications.
The medicinal product is indicated in adults for the treatment of the following infections:
• Acute bacterial sinusitis.
- Exacerbations of chronic obstructive pulmonary disease, including bronchitis.
- Community-acquired pneumonia.
- Complicated skin and soft tissue infections.
- Uncomplicated cystitis.
The medicinal product should be used only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of these infections.
- Acute pyelonephritis and complicated urinary tract infections.
- Chronic bacterial prostatitis.
- Pulmonary form of anthrax: post-exposure prophylaxis and treatment.
The medicinal product may also be used to complete a course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment.
Official recommendations for appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to levofloxacin, other quinolones, or to any component of the medicinal product; epilepsy; history of adverse reactions affecting tendons following previous use of quinolones; in children and adolescents; during pregnancy; during breastfeeding.
Interaction with other medicinal products and other forms of interaction.
Effect of other medicinal products on the medicinal product
Iron salts, antacids containing magnesium and aluminium, zinc salts, didanosine
Absorption of levofloxacin is significantly reduced when iron salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium- or magnesium-containing buffering agents) are taken concomitantly with levofloxacin tablets. Concomitant administration of fluoroquinolones with multivitamins containing zinc results in reduced oral absorption. It is not recommended to take medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium- or magnesium-containing buffering agents), within 2 hours before or after administration of levofloxacin (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 the medicinal product is administered concomitantly with sucralfate. If a patient needs to receive both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after levofloxacin administration (see section "Dosage and administration").
Theophylline, fenbufen, or other similar nonsteroidal anti-inflammatory drugs
No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, nonsteroidal anti-inflammatory drugs, and other medicinal products that reduce the seizure threshold. It is known that levofloxacin concentrations are approximately 13% higher in the presence of fenbufen than when levofloxacin is 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 medicinal products are capable of blocking tubular secretion of levofloxacin. However, in the case of doses tested during the study, it is unlikely that statistically significant kinetic differences would have clinical significance. 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
Calcium carbonate, digoxin, glyburide, and ranitidine do not show any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly.
Effect of the medicinal product 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 tests (PT/INR) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving vitamin K antagonists concomitantly should be monitored for coagulation parameters (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 antipsychotics) (see section "Special precautions for use" (QT interval prolongation)).
Other important information
No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the 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, levofloxacin tablets may be taken independently of food intake.
Special precautions for use.
The use of the drug should be avoided in patients who have experienced serious reactions in the past when taking quinolones or fluoroquinolones. Treatment of such patients with levofloxacin should be initiated only if there are no alternative treatment options and after careful assessment of benefit/risk ratio.
Long-term, disabling and potentially irreversible serious adverse reactions
Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, long-term (lasting months or years), disabling and potentially serious adverse reactions affecting various, and sometimes several simultaneously, organ systems (particularly 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.
Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to fluoroquinolones, including levofloxacin; therefore, levofloxacin is not recommended for treatment of infections caused by MRSA, except when microbial susceptibility to levofloxacin has been confirmed.
Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis, provided these infections have been appropriately diagnosed.
The most common pathogen in urinary tract infections may be E. coli resistant to levofloxacin, which should be taken into account when prescribing levofloxacin to patients with
complicated and uncomplicated urinary tract infections (including pyelonephritis).
For inhalational anthrax, use of levofloxacin 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 consensus guidelines on 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 with organ transplants, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.
At the first signs of tendinitis (painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.
Clostridium difficile-associated disease
Diarrhea, especially severe, persistent, and/or hemorrhagic, during or after treatment with the drug (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD may vary 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 diarrhea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, the drug should be discontinued immediately and appropriate therapy initiated without delay. Antiperistaltic agents are contraindicated in this clinical situation.
Patients prone to seizures
Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients prone to seizures or when used concomitantly with substances that lower the cerebral seizure threshold, such as theophylline. If seizures occur, treatment with 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 susceptible to hemolytic reactions during treatment with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients.
Patients with renal impairment
Since levofloxacin is primarily excreted by 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) after administration of the initial dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.
Severe skin adverse reactions
Severe skin adverse reactions such as toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens–Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported during levofloxacin use, which may be life-threatening or fatal (see section "Adive reactions"). Patients should be informed of the signs and symptoms of these severe skin reactions, and close monitoring should be maintained during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Reinitiation of levofloxacin treatment is contraindicated in patients who have experienced a serious reaction such as Stevens–Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during prior levofloxacin use.
Alterations in blood glucose levels
Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported during treatment with quinolones, particularly in patients with diabetes mellitus receiving concomitant oral hypoglycemic agents (including glyburide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in patients with diabetes mellitus (see section "Adverse reactions").
Prevention of photosensitization
Although photosensitization is very rare with levofloxacin, to avoid it, patients should be advised not to expose themselves unnecessarily 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 parameters (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), monitoring of coagulation parameters is recommended (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 reactions progressed to suicidal ideation and self-destructive 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. Caution is recommended when prescribing levofloxacin to patients with psychiatric 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 long QT syndrome;
- concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides);
- uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
- advanced age;
- cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration" (Elderly patients), "Adverse reactions", "Overdose").
Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patients.
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should be advised to inform their physician promptly to prevent the development of potentially irreversible conditions.
Laboratory tests
In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.
Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may result in false-negative bacteriological test results in patients with tuberculosis.
Hepatobiliary disorders
Cases of necrotic hepatitis, up to life-threatening 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 seek medical advice if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Myasthenia gravis
Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported in the post-marketing period in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.
Visual disturbances
If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").
Superinfection
With the use of levofloxacin, particularly prolonged use, opportunistic infections and overgrowth of resistant microorganisms may occur. Appropriate measures should be taken if secondary infection develops.
Impact on laboratory tests
In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.
Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may result in false-negative bacteriological test results in patients with tuberculosis.
Aortic aneurysm and dissection, valvular regurgitation/incompetence
Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/incompetence 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 family history of aneurysm or congenital heart valve defect, or in patients with diagnosed aortic aneurysm and/or dissection, or valvular heart disease, or in the presence of other risk factors or predisposing conditions:
- for both aortic aneurysm/dissection and valvular regurgitation/incompetence (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, diagnosed atherosclerosis, or Sjögren’s syndrome), or additionally,
- for valvular regurgitation/incompetence (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 case of sudden abdominal, chest, or back pain.
Patients should be advised to seek immediate medical help if acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema occurs.
Use during pregnancy or breastfeeding
Pregnancy. Due to the lack of clinical studies and the potential for quinolones to damage developing cartilage, the drug is contraindicated during pregnancy and breastfeeding. If pregnancy is diagnosed during treatment with the drug, the physician should be informed.
Breastfeeding period. Levofloxacin is contraindicated during breastfeeding. Data on the excretion of levofloxacin into human breast milk are insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage developing cartilage, levofloxacin should not be administered to women who are breastfeeding.
Fertility. Levofloxacin did not cause disorders of fertility or reproductive function in rats.
Ability to influence reaction rate when driving or operating machinery
Patients who drive vehicles or operate machinery should be aware of possible adverse effects on the nervous system (dizziness, vertigo, somnolence, confusion, visual and hearing disturbances, motor disturbances, including gait disturbances).
Method of administration and dosage.
The medication should be taken 1 or 2 times daily. Dosage depends on the type and severity of infection, as well as on the susceptibility of the potential causative agent to the drug.
The medication may also be used to complete a course of therapy in patients who have shown improvement during initial intravenous treatment with levofloxacin; considering the bioequivalence of parenteral and oral forms, the same dosage may be used.
Dosage. The following dosage recommendations may be provided for the medication:
Table 3
Dosage for adult patients with normal renal function (creatinine clearance exceeding 50 ml/min)
| Indications |
Daily dose (depending on severity) |
Duration of treatment (depending on severity) |
| Acute bacterial sinusitis |
500 mg once daily |
10–14 days |
| Exacerbation of chronic obstructive pulmonary disease, including bronchitis |
500 mg once daily |
7–10 days |
| Community-acquired pneumonia |
500 mg 1–2 times daily |
7–14 days |
| Acute pyelonephritis |
500 mg once daily |
7–10 days |
| Complicated urinary tract infections |
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 daily |
7–14 days |
| Pulmonary form of anthrax |
500 mg once daily |
8 weeks |
Table 4
Dosing for patients with impaired renal function (creatinine clearance less than 50 ml/min)
| Creatinine clearance, mL/min |
Dosing regimen (depending on severity of infection and nosological form) |
||
| 50–20 |
250 mg/24 hours |
500 mg/24 hours |
500 mg/12 hours |
| initial dose – 250 mg, subsequent – 125 mg/24 hours |
initial dose – 500 mg, subsequent – 250 mg/24 hours |
initial dose – 500 mg, subsequent – 250 mg/12 hours |
|
| 19–10 |
initial dose – 250 mg, subsequent – 125 mg/48 hours |
initial dose – 500 mg, subsequent – 125 mg/24 hours |
initial dose – 500 mg, subsequent – 125 mg/12 hours |
| <10 (also in hemodialysis and CRRT 1) |
initial dose – 250 mg, subsequent – 125 mg/48 hours |
initial dose – 500 mg, subsequent – 125 mg/24 hours |
initial dose – 500 mg, subsequent – 125 mg/24 hours |
1 After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.
Dosing 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.
Dosing in elderly patients . If renal function is not impaired, dose adjustment is not required (see section "Special precautions": Tendinitis and tendon rupture. QT interval prolongation).
Method of administration
Tablets should be swallowed whole with sufficient fluid. Tablets may be taken during or between meals. The drug should be administered at least 2 hours before or after the administration of iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for didanosine formulations containing aluminum- or magnesium-containing buffering agents) and sucralfate, as reduced absorption may occur.
Children.
The use of the drug is contraindicated in children (under 18 years of age), as damage to the articular cartilage cannot be excluded.
Overdose.
According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic, the most important signs expected after acute levofloxacin overdose 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, effects on the central nervous system have been observed, including confusion, convulsions, hallucinations, and tremor.
In case of overdose, symptomatic treatment should be initiated. ECG monitoring should be performed, as QT interval prolongation is possible. 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.
Adverse reactions
The information below is based on data from clinical trials involving more than 8300 patients and on post-marketing experience.
Frequency is defined according to the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).
Within each group, adverse reactions are listed in order of decreasing severity.
Table 5
| Body systems and organs |
Common |
Uncommon |
Rare |
Frequency unknown |
| Infections and infestations |
fungal infections, including Candida species, resistance of pathogenic microorganisms |
|||
| Blood and lymphatic system disorders |
leukopenia, eosinophilia |
thrombocytopenia, neutropenia |
pancytopenia, agranulocytosis, hemolytic anemia |
|
| Immune system disorders |
angioedema, hypersensitivity (see section "Special precautions") |
anaphylactic/ anaphylactoid shock (see section "Special precautions"), anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose |
||
| Metabolism and nutrition disorders |
anorexia |
hypoglycemia, mainly in diabetic patients (see section "Special precautions") |
hyperglycemia, hypoglycemic coma (see section "Special precautions") |
|
| Psychiatric disorders* |
insomnia |
anxiety, confusion, restlessness, nervousness, |
psychotic reactions (including hallucinations, paranoia), depression, agitation, uneasiness, unusual dreams, night terrors |
Psychotic reactions with self-destructive behaviour, including suicidal thoughts or actions (see section "Special precautions"). |
| Nervous system disorders* |
headache, dizziness |
drowsiness, tremor, dysgeusia (subjective taste disturbance) |
seizures (see section "Contraindications" and "Special precautions"), paraesthesia |
peripheral sensory or sensorimotor neuropathy (see section "Special precautions"), smell disorders (parosmia), including anosmia (loss of smell), dyskinesia (movement coordination disorders), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hypertension |
| Eye disorders* |
visual disturbances, such as blurred vision (see section "Special precautions") |
temporary vision loss (see section "Special precautions"), uveitis |
||
| Ear and labyrinth disorders* |
vertigo |
tinnitus |
hearing loss, hearing impairment |
|
| 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), prolongation of the QT interval on electrocardiogram (see sections "Special precautions": QT interval prolongation and "Overdose") |
||
| Vascular disorders** |
phlebitis (applies to injectable forms) |
arterial hypotension |
||
| Respiratory system disorders |
dyspnea (shortness of breath) |
bronchospasm, allergic pneumonitis |
||
| Gastrointestinal disorders |
diarrhea, vomiting, nausea |
abdominal pain, dyspepsia, abdominal distension, constipation |
hemorrhagic diarrhea, rarely indicating enterocolitis, including pseudomembranous colitis (see section "Special precautions"), pancreatitis |
|
| Hepatobiliary disorders |
elevation of 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 precautions") hepatitis |
|
| Skin and subcutaneous tissue disorders |
rash, pruritus, urticaria, hyperhidrosis |
drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions), fixed drug eruption |
toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, multiform erythema, photosensitivity reactions (see section "Special precautions"), leukocytoclastic vasculitis, stomatitis |
|
| Musculoskeletal and connective tissue disorders* |
arthralgia, myalgia |
tendon disorders (see section "Special precautions"), including tendon inflammation (tendinitis) (e.g., Achilles tendon); muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special precautions") |
muscle disorders (rhabdomyolysis), tendon rupture (e.g., Achilles tendon: see section "Special precautions"), ligament rupture, muscle rupture, arthritis |
|
| 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) |
|||
| General disorders and administration site conditions* |
infusion site reactions (pain, redness) |
asthenia |
pyrexia |
pain (including back, chest and 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.
Other adverse effects associated with the use of fluoroquinolones include:
- extrapyramidal symptoms and other movement coordination disorders;
- hypersensitivity vasculitis;
- attacks of porphyria in patients with existing porphyria.
* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported long-term (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various systems of the body and sensory organs, sometimes several simultaneously (including reactions such as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbances, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, disturbances in hearing, vision, taste, and smell).
** Cases of aneurysms and dissections of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any of the heart valves have been reported in patients treated with fluoroquinolones (see section "Special precautions").
Shelf life. 3 years.
Storage conditions.
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging.
10 tablets per blister. 3 blisters per cardboard box.
Prescription status. By prescription only.
Manufacturer.
Jubilant Generics Limited.
Manufacturer's address and location of its business operations.
Village Sikandarpur, Bhainswal, Roorkee-Dehradun Road, Bhagwanpur, Roorkee, District Haridwar, Uttarakhand, IN-247661, India.