Levofloxacin-astrapharm
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN-ASTRAPHARM (LEVOFLOXACIN-ASTRAPHARM)
Composition:
Active substance: levofloxacin;
One tablet contains levofloxacin 250 mg or 500 mg;
Excipients: crospovidone, microcrystalline cellulose, sodium stearyl fumarate, coating "SelecCoat™" (hypromellose, polyethylene glycol 6000, titanium dioxide (E 171)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: oval-shaped, biconvex film-coated tablets of white color.
Pharmacotherapeutic group
Antibacterials for systemic use. Fluoroquinolones. ATC code J01MA12.
Pharmacological Properties
Pharmacodynamics
Levofloxacin is a synthetic antibiotic from the fluoroquinolone class. It is the S(-) enantiomer of the racemic active substance ofloxacin.
Mechanism of action
As a fluoroquinolone-class antibacterial agent, levofloxacin acts on the DNA-DNA gyrase and topoisomerase IV complex.
Pharmacokinetics / Pharmacodynamics (PK/PD)
The bactericidal activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) to the minimum inhibitory concentration (MIC), or the ratio of the area under the concentration-time curve (AUC) to MIC.
Mechanism of resistance
Resistance to levofloxacin develops stepwise through mutations in the binding regions of two types of type II topoisomerases – DNA gyrase and topoisomerase IV. Other mechanisms may also play a role, including reduced permeability of the cell membrane (often in Pseudomonas aeruginosa) and active efflux from the cell (efflux).
Cross-resistance exists between levofloxacin and other fluoroquinolones. Due to its specific mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.
Breakpoint values
The EUCAST recommended breakpoint values for levofloxacin, which distinguish susceptible strains from moderately susceptible strains and moderately susceptible strains from resistant strains, are presented in Table 1 (mg/L).
Table 1
EUCAST breakpoint values for levofloxacin (version 10.0, 01-01-2020):
| Organism |
Susceptible |
Resistant |
| Enterobacteriaceae |
≤ 0.5 mg/L |
> 1 mg/L |
| Pseudomonas spp. |
≤ 0.001 mg/L |
> 1 mg/L |
| Acinetobacter spp. |
≤ 0.5 mg/L |
> 1 mg/L |
| Staphylococcus aureus# Staphylococcus coagulase-negative |
≤ 0.001 mg/L |
> 1 mg/L |
| Enterococcus spp.¹ |
≤ 4 mg/L |
> 4 mg/L |
| Streptococcus pneumoniae |
≤ 0.001 mg/L |
> 2 mg/L |
| Streptococcus spp., groups A, B, C, G |
≤ 0.001 mg/L |
> 2 mg/L |
| Haemophilus influenzae |
≤ 0.06 mg/L |
> 0.06 mg/L |
| Moraxella catarrhalis |
≤ 0.125 mg/L |
> 0.125 mg/L |
| Helicobacter pylori |
≤ 1 mg/L |
> 1 mg/L |
| Aerococcus sanguinicola & A. urinae² |
≤ 2 mg/L |
> 2 mg/L |
| Aeromonas spp. |
≤ 0.5 mg/L |
> 1 mg/L |
| Non-species-related breakpoints |
≤ 0.5 mg/L |
> 1 mg/L |
1Only uncomplicated urinary tract infections.
2Susceptibility can be inferred based on sensitivity to ciprofloxacin.
Resistance prevalence may vary geographically and over time for specific species. Information on local resistance prevalence is useful, especially for the treatment of severe infections. When necessary, consultation with a specialist is advisable, particularly when the efficacy of the drug against certain infections may be questionable due to local resistance prevalence.
Typically susceptible microorganisms:
Gram-positive aerobic bacteria:
Bacillus anthracis, Staphylococcus aureus (MRSA)#, Staphylococcus saprophyticus, group C and G streptococci, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.
Gram-negative aerobic bacteria:
Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.
Anaerobes:
Peptostreptococcus.
Others:
Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.
Occasionally susceptible (resistance > 10 %):
Gram-positive: Enterococcus faecalis, Staphylococcus aureus (MRSA), coagulase-negative staphylococci.
Gram-negative: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.
Anaerobes: Bacteroides fragilis.
Naturally resistant microorganisms:
Enterococcus faecium.
#Methicillin-resistant Staphylococcus aureus (MRSA) often exhibits cross-resistance to fluoroquinolones, including levofloxacin.
Pharmacokinetics
Absorption
After oral administration, levofloxacin is rapidly and almost completely absorbed. The maximum plasma concentration (Cmax) is observed within 1–2 hours after administration. Absolute bioavailability is 99–100%.
Food has minimal effect on levofloxacin absorption.
Steady-state is achieved within 48 hours after administration 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 extensive distribution into body tissues.
Penetration into tissues and body fluids
Levofloxacin has been shown to penetrate bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicular fluid), prostate tissue, and urine. However, penetration of levofloxacin into cerebrospinal fluid is low.
Metabolism
Levofloxacin is minimally metabolized, with metabolites being desmethyl-levofloxacin and levofloxacin-N-oxide. These metabolites account for less than 5% of the drug excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination
After oral administration or intravenous infusion, 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).
The mean apparent total body clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min.
There is no significant difference between the pharmacokinetics of levofloxacin after oral administration or intravenous infusion, indicating interchangeability of oral and intravenous routes of administration.
Linearity
Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 1000 mg.
Special patient groups
Patients with renal impairment
Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, elimination and clearance are reduced, and elimination half-life is prolonged, as shown in Table 2.
Table 2
Pharmacokinetics in patients with renal impairment after a single oral dose of 500 mg
| 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 between young patients and elderly patients, except for differences in creatinine clearance.
Gender-related Differences
Separate analysis for men and women showed minor or negligible gender-related differences in the pharmacokinetics of levofloxacin. There is no evidence that these gender-related differences are of clinical significance.
Clinical characteristics
Indications
Levofloxacin-Astrafarm is indicated for the treatment in adults of the following infections caused by microorganisms sensitive to levofloxacin:
- acute bacterial sinusitis;
- acute exacerbation of chronic obstructive pulmonary disease, including bronchitis;
- community-acquired pneumonia;
- complicated skin and soft tissue infections;
- uncomplicated cystitis
(when treating the above-mentioned infections, the drug should be used only when other antibacterial agents typically prescribed for initial treatment of these infections are not feasible);
- complicated urinary tract infections (including acute pyelonephritis);
- chronic bacterial prostatitis.
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications
Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the medicinal product.
Epilepsy.
History of tendon damage associated with fluoroquinolone use.
Children and adolescents under 18 years of age.
Pregnancy or breastfeeding.
Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on levofloxacin
Iron salts, antacids containing magnesium and aluminum, didanosine
Absorption of levofloxacin is significantly reduced when co-administered with iron salts, antacids containing magnesium or aluminum, or didanosine (only didanosine formulations with buffering agents containing aluminum or magnesium). Concurrent use of fluoroquinolones with multivitamins containing zinc reduces their oral absorption.
Concomitant use of medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (this applies only to didanosine formulations containing buffering agents of aluminum or magnesium), is not recommended within 2 hours before or after oral administration of levofloxacin tablets (see section "Dosage and administration").
Calcium salts have minimal effect on the oral absorption of levofloxacin.
Sucralfate
The bioavailability of levofloxacin 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 Levofloxacin-Astrafarm tablets.
Theophylline, fenbufen, or similar nonsteroidal 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, nonsteroidal anti-inflammatory drugs, and other agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher in the presence of fenbufen compared to administration of levofloxacin alone.
Probenecid and cimetidine
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.
Renal clearance of levofloxacin decreases by 24% in the presence of cimetidine and by 34% with probenecid. This is explained by the ability of both drugs to block tubular secretion of levofloxacin. However, in studies, statistically significant kinetic differences did not have clinical significance. Concomitant use of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be done with caution, especially in patients with renal impairment.
Other medicinal products
Studies have shown that the following medicinal products do not cause any clinically significant effect on the pharmacokinetics of levofloxacin: calcium carbonate, digoxin, glyburide, ranitidine.
Effect of levofloxacin on other medicinal products
Cyclosporine
The elimination half-life of cyclosporine increases by 33% when co-administered with levofloxacin.
Vitamin K antagonists
When used concomitantly with vitamin K antagonists (e.g., warfarin), increased international normalized ratio (INR) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concomitantly.
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).
Other information
In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (a probe substrate for CYP1A2), indicating that levofloxacin is not an inhibitor of CYP1A2.
Food intake
No clinically significant interaction with food has been observed; therefore, Levofloxacin-Astrafarm tablets may be taken independently of food intake.
Special precautions for use
The use of levofloxacin should be avoided in patients who have experienced serious adverse reactions to previously administered medicinal products containing quinolones or fluoroquinolones (see section "Contraindications"). Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Adverse reactions").
Methicillin-resistant S. aureus
For methicillin-resistant S. aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. 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 (and when use of usually recommended antibacterial agents for MRSA infections is considered impossible).
Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis, provided these infections have been correctly diagnosed.
Resistance to fluoroquinolones in E. coli (the most common cause of urinary tract infections) varies across different countries. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.
Tendinitis and tendon rupture
Tendinitis and tendon rupture (particularly of the Achilles tendon, but not limited to it), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones, and even several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients with transplanted parenchymal organs, patients receiving a daily dose of 1000 mg levofloxacin, and in patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided. At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued and alternative therapy considered. The affected limb 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 receiving 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. If myoclonus occurs, levofloxacin should be discontinued immediately and appropriate treatment initiated.
Clostridium difficile-associated disease
Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The severity of Clostridium difficile-associated disease may range from mild to life-threatening; the most severe form is pseudomembranous colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected or confirmed, the medicinal product should be discontinued immediately and appropriate treatment initiated without delay. Medicinal products that inhibit intestinal motility 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. As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures or receiving concomitant treatment with active substances that lower the 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, with monitoring for possible development of hemolysis.
Patients with renal impairment
Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency).
Hypersensitivity reactions
Levofloxacin may cause severe hypersensitivity reactions (e.g., angioedema up to anaphylactic shock), which sometimes occur after the first dose. In such cases, patients should discontinue treatment immediately and seek medical advice.
Severe skin reactions
Severe skin reactions have been reported with levofloxacin, 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 lead to fatal outcomes.
During treatment, patients should be informed about the signs of severe skin reactions and closely monitored.
At the first signs of such reactions, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient experiences a serious skin reaction such as TEN, SJS, or DRESS during treatment with levofloxacin, this medicinal product should not be prescribed again in the future.
Dysglycemia
During treatment with levofloxacin, as with other quinolones, fluctuations in blood glucose levels have been reported, including cases of hyperglycemia and hypoglycemia, particularly in patients with diabetes mellitus 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 changes in blood glucose levels occur, treatment with levofloxacin should be discontinued immediately, and alternative antibiotic therapy not belonging to the fluoroquinolone class should be considered.
Phototoxicity prevention
Although phototoxicity is very rare with levofloxacin, to avoid it, patients should avoid exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment with levofloxacin and for 48 hours after discontinuation of levofloxacin.
Patients receiving vitamin K antagonists
Due to the possible increase in INR and/or bleeding in patients taking levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation test results should be monitored in such cases.
Psychotic reactions
Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, these reactions progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in 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;
- 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, antipsychotic drugs);
- uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
- heart disease (e.g., heart failure, myocardial infarction, bradycardia).
Elderly patients and younger women may be more sensitive to medicinal products that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups.
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.
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or muscle weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or muscle weakness occur, patients should be advised to inform their physician promptly to prevent potentially irreversible damage.
Hepatobiliary disorders
Cases of necrotic hepatitis, up to life-threatening liver failure, 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 seek medical advice if signs of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Laboratory tests
In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate test results using specific methods may be necessary.
Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may result in a false-negative bacteriological test result in patients with tuberculosis.
Aortic aneurysm or dissection and cardiac valve regurgitation/insufficiency
Epidemiological studies have shown 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 regurgitation/insufficiency of any cardiac valve have been reported in patients receiving 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 defect, or in patients with an existing diagnosis of aneurysm and/or aortic dissection, or with heart valve disease, or in the presence of other risk factors or predisposing conditions
- both for aortic aneurysm and dissection and for cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, vascular type Ehlers-Danlos syndrome or Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis) or additionally
- for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome) or additionally
§ for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).
The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving systemic corticosteroids concomitantly.
In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention at an emergency department.
Patients should be advised to seek immediate medical help if acute shortness of breath, a new episode of palpitations, or development of abdominal or lower limb edema occurs.
Long-term, disabling, and potentially irreversible serious adverse reactions
In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous system, mental health, sensory organs) have been observed regardless of age or presence of risk factors. Patients should be advised to discontinue levofloxacin immediately if the first symptoms of any serious adverse reaction occur and to consult a physician.
Myasthenia gravis
Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with Myasthenia gravis. Serious adverse reactions, including fatal cases and need for respiratory support, have been reported in post-marketing experience in patients with Myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of Myasthenia gravis.
Visual disorders
If visual disturbances or other ocular effects occur, immediate consultation with an ophthalmologist is required (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse reactions").
Superinfection
With the use of levofloxacin, particularly prolonged use, development of opportunistic infections and overgrowth of resistant microorganisms is possible. Appropriate measures should be taken if secondary infection develops.
Acute pancreatitis
Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should seek immediate medical attention. If acute pancreatitis is suspected, levofloxacin should be discontinued. If acute pancreatitis is confirmed, levofloxacin should not be restarted. Caution is required in patients with a history of pancreatitis (see section "Adverse reactions").
Excipients
The medicinal product Levofloxacin-Astrafarm contains sodium stearyl fumarate. Caution should be exercised when administering to patients on a sodium-controlled diet.
Use during pregnancy or breastfeeding
Pregnancy
Data on the use of levofloxacin in pregnant women are limited. Animal studies have not shown any direct or indirect harmful effects on reproductive function. Due to the lack of human studies and the potential for quinolones to damage the articular cartilage in the growing organism, the medicinal product should not be administered during pregnancy. If pregnancy occurs during treatment, this should be reported to the physician.
Breastfeeding
The medicinal product Levofloxacin-Astrafarm is contraindicated in women who are breastfeeding. There is insufficient data on the excretion of levofloxacin into breast milk. However, other fluoroquinolones are excreted in breast milk. Due to the lack of human data and the risk of fluoroquinolone-induced damage to weight-bearing joint cartilage in the growing organism based on experimental data, levofloxacin should not be used in women who are breastfeeding.
Fertility
Levofloxacin did not impair fertility or reproductive performance in rats.
Ability to influence reaction speed when driving or operating machinery
The medicinal product Levofloxacin-Astrafarm has a negligible or moderate effect on the ability to drive or operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair the patient's ability to concentrate and react and thus may pose a risk in situations where these abilities are particularly important (e.g., driving a vehicle or operating machinery).
Dosage and Administration
The drug should be taken 1–2 times daily. The dose depends on the type and severity of infection and the susceptibility of the likely pathogen.
Tablets may be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin in intravenous form, using the same dosage regimen, taking into account the bioequivalence of the parenteral and oral forms of the drug.
Tablets should be swallowed whole with sufficient fluid. The drug may be taken regardless of food intake.
The drug should be administered at least 2 hours before or 2 hours after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only formulations containing aluminum or magnesium in buffering agents), and sucralfate (see section "Interaction with other medicinal products and other types of interactions").
Table 3
Dosage for adult patients with normal renal function, in whom creatinine clearance is over 50 mL/min:
| Indications |
Dose, mg |
Number of doses per day, times |
Duration of treatment, days |
| Acute bacterial sinusitis |
500 |
1 |
10–14 |
| Exacerbation of chronic obstructive pulmonary disease, including bronchitis |
500 |
1 |
7–10 |
| Community-acquired pneumonia |
500 |
1–2 |
7–14 |
| Uncomplicated cystitis |
250 |
1 |
3 |
| Chronic bacterial prostatitis |
500 |
1 |
28 |
| Complicated urinary tract infections |
500 |
1 |
7–14 |
| Acute pyelonephritis |
500 |
1 |
7–10 |
| Complicated skin and soft tissue infections |
500 |
1–2 |
7–14 |
Table 4
Dosage for patients with impaired renal function in whom creatinine clearance is less than 50 ml/min
| Creatinine clearance |
Dosing regimen (depending on the severity of infection) |
||
| 50–20 mL/min |
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 mL/min |
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 mL/min (including hemodialysis and CAPD1) |
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 |
1After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.
The tablets are not intended to be divided. If a lower dose is required, levofloxacin in another pharmaceutical form should be used.
Dosing in patients with hepatic impairment
Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver.
Dosing in elderly patients
If renal function is not impaired, dose adjustment is not required.
Children
Levofloxacin-AstraPharm is contraindicated in children, as damage to joint cartilage cannot be excluded.
Overdose
Symptoms: dizziness, impaired consciousness, seizures, nausea, and erosion of mucous membranes.
During the post-marketing period, adverse events involving the central nervous system have been observed, including confusion, convulsions, myoclonus, hallucinations, and tremor. According to study results, administration of doses higher than therapeutic ones has been associated with QT interval prolongation.
Treatment: symptomatic and supportive care. ECG monitoring should be considered due to the potential for QT interval prolongation. Antacids may be used to protect the gastric mucosa. Levofloxacin is not eliminated by either hemodialysis or peritoneal dialysis; there is no specific antidote.
Adverse reactions
The frequency of adverse reactions listed below was determined using the following criteria: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).
Within each frequency group, adverse reactions are listed in order of decreasing severity.
Table 5
Adverse Reactions
| System organ |
Common (≥ 1/100 to < 1/10) |
Uncommon (≥ 1/1000 to < 1/100) |
Rare (≥ 1/10000 to < 1/1000) |
Frequency not known (cannot be estimated from available data) |
| Infections and infestations Pathogen resistance |
Fungal infections, including Candida infections, resistance of pathogenic microorganisms |
|||
| Blood and lymphatic system disorders |
Leukopenia, eosinophilia |
Thrombocytopenia, neutropenia |
Aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia |
|
| Immune system disorders |
Angioneurotic edema, hypersensitivity |
Anaphylactic shock, anaphylactoid reaction |
||
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
|||
| Metabolism and nutrition disorders |
Anorexia |
Hypoglycemia, especially in diabetic patients; hypoglycemic coma |
Hyperglycemia |
|
| Psychiatric disorders* |
Insomnia |
Anxiety, confusion, restlessness |
Psychotic reactions (e.g., hallucinations, paranoia), depression, agitation, unusual dreams, nightmares, delirium |
Psychotic disorders with self-harm, including suicidal ideation or suicide attempts, mania |
| Nervous system disorders* |
Headache, dizziness |
Somnolence, tremor, dysgeusia |
Seizures, paraesthesia, memory problems |
Peripheral sensory neuropathy (see section "Special warnings and precautions for use"); peripheral sensorimotor neuropathy (see section "Special warnings and precautions for use"); parosmia, including anosmia; dyskinesia; extrapyramidal disorder; ageusia; syncope; benign intracranial hypertension; myoclonus |
| Eye disorders* |
Visual disturbances such as blurred vision |
Transient vision loss, uveitis |
||
| Ear and labyrinth disorders* |
Dizziness |
Tinnitus |
Hearing loss, hearing impairment |
|
| Cardiac disorders** |
Tachycardia, palpitations |
Ventricular tachycardia which may lead to cardiac arrest; ventricular arrhythmia and torsade de pointes (reported mainly in patients with risk factors for QT prolongation), QT interval prolongation confirmed by electrocardiogram |
||
| Vascular disorders** |
Arterial hypotension |
|||
| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
Bronchospasm, allergic pneumonia |
||
| Gastrointestinal disorders |
Diarrhea, vomiting, nausea |
Abdominal pain, dyspepsia, flatulence, constipation |
Hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis; pancreatitis |
|
| Hepatobiliary disorders |
Increased liver enzymes (ALAT/ASAT, alkaline phosphatase, gamma GT) |
Elevated blood bilirubin |
Jaundice and severe liver injury, including fatal cases of acute liver failure, mainly in patients with serious underlying conditions; hepatitis |
|
| Skin and subcutaneous tissue disorders |
Itchy rash, urticaria, hyperhidrosis |
Drug reaction with eosinophilia and systemic symptoms (DRESS), fixed drug eruption |
Toxic epidermal necrolysis; Stevens-Johnson syndrome, multiform erythema, photosensitivity reactions, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation |
|
| Musculoskeletal and connective tissue disorders* |
Arthralgia, myalgia |
Tendon disorders, including tendinitis (e.g., Achilles tendon); muscle weakness, which may be particularly important in patients with myasthenia gravis |
Rhabdomyolysis; tendon rupture (e.g., Achilles tendon); ligament rupture; muscle rupture; arthritis |
|
| Renal and urinary disorders |
Increased serum creatinine |
Acute renal failure (e.g., due to interstitial nephritis) |
||
| General disorders and administration site conditions* |
Asthenia |
Pyrexia |
Pain (especially back, chest and limb pain) |
aAnaphylactic and anaphylactoid reactions may sometimes occur after administration of the first dose.
bSkin and mucous membrane reactions may sometimes occur after administration of the first dose.
Other adverse reactions associated with the use of fluoroquinolones include porphyria attacks in patients with porphyria.
*Very rare cases of prolonged (for several months or years), disabling and potentially irreversible serious adverse drug reactions have been reported with quinolones and fluoroquinolones, sometimes affecting multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration disturbances, as well as disturbances in hearing, vision, taste, and smell), sometimes occurring in the absence of risk factors (see section "Special precautions for use").
**Cases of aneurysms and aortic dissections, 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 for use").
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
7 tablets in a blister; 1 or 2 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer
ASTRAFARM LLC, Ukraine.
Manufacturer's address and place of business
6, Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, 08132, Ukraine