Remedia
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT Remedia (remedia)
Composition:
Active substance: levofloxacin;
1 tablet contains levofloxacin (as levofloxacin hemihydrate) 250 mg or 500 mg;
Excipients: microcrystalline cellulose, povidone K-30, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, sodium lauryl sulfate, propylene glycol, coating Protectab HP-1: hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical characteristics: elongated biconvex yellow film-coated tablets, with a break line on one side.
Pharmacotherapeutic group.
Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01M A12.
Pharmacological properties.
Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent from the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin. As an antibacterial agent from the fluoroquinolone group, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.
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 concentration (MIC).
The primary mechanism of resistance is due to 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 usually does not occur.
The breakpoints for MIC values for levofloxacin, as recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant), and intermediate from resistant organisms, are presented in Table 1 of MIC testing (mg/L).
Table 1
EUCAST clinical breakpoints for levofloxacin MIC
| 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 |
| Non-species-related breakpoints3 |
≤ 1 mg/L |
> 2 mg/L |
| 1 The MIC breakpoint between susceptible and intermediately susceptible (moderately resistant) strains has been increased from 1 to 2 mg/L to inhibit growth of wild-type strains of this microorganism exhibiting variability in this parameter. The breakpoints apply to high-dose therapy. 2 Strains with MIC values above the breakpoint between susceptible and intermediately susceptible (moderately resistant) strains are very rare or have not been reported. Testing for identification and antimicrobial susceptibility of any such isolate should be repeated, and if confirmed, the isolate should be sent to a reference laboratory. 3 Non-species-related MIC breakpoints were primarily determined based on pharmacokinetic/pharmacodynamic data and are independent of the MIC distribution of specific species. Non-species-related MIC breakpoints are used only for species for which no species-specific breakpoint has been defined, and are not used for species for which susceptibility testing is not recommended or for which there is insufficient evidence for doubtful species (Enterococcus, Neisseria, Gram-negative anaerobes). |
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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 Table 4 for MIC testing (µg/mL) or disk diffusion method (zone diameter [mm] using a 5-µg levofloxacin disk).
Table 2
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 |
| β-hemolytic Streptococcus |
≤ 2 µg/mL ≥17 mm |
≥ 8 µg/mL ≤ 13 mm |
| 1 The absence or rare occurrence of resistant strains precludes the definition of any categories of results 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
The prevalence of resistance in selected species may vary geographically and over time. Local information on resistance is desirable, especially when treating severe infections. Advice should be sought from a specialist when local resistance prevalence renders the usefulness of the agent at least questionable for certain types of infections.
Typically sensitive species
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 thetaiotaomicron**, Bacteroides vulgatus**, Clostridium difficile**
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
** Naturally intermediate 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 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 serum. Cumulative effect with repeated administration of levofloxacin 500 mg once daily is virtually absent. A slight but predictable cumulative effect occurs after repeated doses of 500 mg twice daily. Steady state is 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 concentrations of levofloxacin in lung tissue after a 500 mg oral dose were 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 during 3 days of treatment with 500 mg once or twice daily, respectively.
Penetration into cerebrospinal (CSF) fluid
Levofloxacin penetrates poorly into cerebrospinal fluid.
Penetration into prostate tissue
After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue reached 8.7 µg/g, 8.2 µg/g, and 2.0 µg/g at 2 hours, 6 hours, and 24 hours, respectively. The mean prostate/plasma concentration ratio was 1.84.
Urine concentration
Mean urine concentrations 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg levofloxacin were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.
Biological transformation
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 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 these routes (oral and intravenous) are interchangeable.
Linearity
Levofloxacin exhibits linear pharmacokinetics in the range of 50–600 mg.
Patients with renal impairment
Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-lives increase, as shown in Table 3.
Table 3
| Creatinine clearance (ml/min) |
< 20 |
20–40 |
50–80 |
| Renal clearance (ml/min) |
13 |
26 |
57 |
| Half-life (hours) |
35 |
27 |
9 |
Geriatric patients
There are no significant differences in the pharmacokinetics of levofloxacin in younger patients and elderly patients, except for differences related to creatinine clearance.
Gender differences
Separate analysis in 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 Remedia is indicated for the treatment in adults of the following infections caused by microorganisms sensitive to levofloxacin:
- acute bacterial sinusitis;
- exacerbations of chronic obstructive pulmonary disease, including bronchitis;
- community-acquired pneumonia;
- complicated skin and soft tissue infections;
- uncomplicated cystitis;
(When treating the above-mentioned infections, the drug should be used only when the use of other antibacterial agents typically prescribed for initial treatment of these infections is not possible)
- complicated urinary tract infections and acute pyelonephritis;
- chronic bacterial prostatitis;
- pulmonary form of anthrax: post-exposure prophylaxis and treatment.
Remedia in this pharmaceutical form (tablets) may be used to complete the course of therapy in patients who have demonstrated improvement during initial treatment with levofloxacin infusion solution.
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to levofloxacin, to other quinolones, or to any component of the drug; epilepsy; history of tendon-related adverse reactions following prior use of quinolones; pediatric age; pregnancy or breastfeeding.
Interaction with other medicinal products and other types of interactions.
Effects of other medicinal products on the drug
Iron salts, antacids containing magnesium and aluminum, didanosine
Absorption of levofloxacin is significantly reduced when iron salts, antacids containing magnesium or aluminum, or didanosine (only formulations containing aluminum or magnesium buffering agents) are taken simultaneously with levofloxacin tablets. Concomitant administration of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption. It is recommended not to use 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 aluminum or magnesium buffering agents), within 2 hours before or after taking levofloxacin tablets (see section "Dosage and administration").
Calcium salts have minimal effect on the absorption of levofloxacin when administered orally.
Sucralfate
The bioavailability of levofloxacin tablets is significantly reduced when 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 use of quinolones with theophylline and nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.
Probenecid and cimetidine
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.
Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both drugs 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. Caution should be exercised when co-administering levofloxacin with medicinal products that affect tubular secretion, such as probenecid and cimetidine, particularly in patients with renal impairment.
Other information
Calcium carbonate, digoxin, glyburide, and ranitidine do not have any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly.
Effects 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), increased coagulation parameters (PT/INR) and/or bleeding events, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section "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, and macrolides) (see section "Precautions for use" (QT interval prolongation)).
Other relevant 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.
Food intake
No clinically significant interaction with food has been observed. Therefore, levofloxacin tablets may be taken regardless of food intake.
Special precautions for use.
The use of levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment of these patients with levofloxacin should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").
For the pulmonary form of anthrax, use is based on in vitro susceptibility data for Bacillus anthracis, animal experimental data, and limited human experience. Physicians should consider national and/or international consensus guidelines on the treatment of anthrax.
Methicillin-resistant S. aureus
There is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections where MRSA is known or suspected, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and when the use of typically 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 appropriately diagnosed.
Resistance to fluoroquinolones in E. coli (the most common causative agent of urinary tract infections) varies across countries. When prescribing fluoroquinolones, the local prevalence of fluoroquinolone resistance in E. coli should be taken into account.
Long-term, disabling and potentially irreversible serious adverse reactions
In patients treated with quinolones and fluoroquinolones, regardless of age or presence of risk factors, very rare cases of prolonged (lasting months or years), disabling and potentially irreversible serious adverse drug reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, psyche, sensory organs) have been observed. Levofloxacin therapy must be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.
Tendinitis and tendon rupture
Tendinitis and tendon ruptures (particularly of the Achilles tendon, but not limited to it), sometimes bilateral, may occur as early as 48 hours after initiation of quinolone or fluoroquinolone therapy, and have been reported even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients receiving 1000 mg levofloxacin daily, patients with impaired renal function, patients after solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant corticosteroid therapy should be avoided.
If early symptoms of tendinitis (e.g., pain, swelling, inflammation) occur, levofloxacin treatment should be discontinued and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilized). Corticosteroids should not be used if signs of tendinopathy occur.
The daily dose should be adjusted in elderly patients based on creatinine clearance. Elderly patients receiving levofloxacin should be closely monitored.
Clostridium difficile-associated disease
Diarrhea, particularly severe, persistent and/or hemorrhagic, during or after treatment with the drug (including within several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. Clostridium difficile-associated disease may range in severity from mild to life-threatening; the most severe form being pseudomembranous colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, the drug should be discontinued immediately, and patients should be urgently managed with supportive measures ± specific therapy (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.
Patients predisposed to seizures
Quinolones may lower the seizure threshold and provoke seizures. The drug 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, particularly those with prior central nervous system disorders, concomitant therapy with phenylbutazone or similar nonsteroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, treatment with levofloxacin should be discontinued.
Patients with glucose-6-phosphate dehydrogenase deficiency
Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency may be susceptible to hemolytic reactions during treatment with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in these patients.
Patients with renal impairment
Since levofloxacin is primarily eliminated 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) after administration of the initial dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed of the signs and symptoms of these severe skin reactions and closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-initiation of levofloxacin in patients who have experienced a serious reaction such as SJS, TEN, or DRESS syndrome is contraindicated.
Alterations in blood glucose levels
Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glyburide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in diabetic patients (see section "Adverse reactions").
Prevention of photosensitization
Although photosensitization occurs very rarely with levofloxacin, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of the drug.
Patients receiving vitamin K antagonists
Due to the potential for increased coagulation test parameters (PT/INR) and/or bleeding in patients receiving levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored (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, such reactions have progressed to suicidal thoughts and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.
QT interval prolongation
Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:
- congenital 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).
Elderly patients and women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using levofloxacin in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration" (Elderly patients), "Overdose", "Adverse reactions").
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop, patients receiving levofloxacin should inform their physician before continuing treatment to prevent the development of potentially irreversible conditions (see section "Adverse reactions").
Hepatobiliary disorders
Cases of non-necrotizing hepatitis, up to life-threatening liver failure, have been reported, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult their physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. In the post-marketing period, severe adverse reactions, including fatal cases and the need for respiratory support, have been reported in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.
Aortic aneurysm and aortic dissection
Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection following fluoroquinolone use, particularly in the elderly.
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative treatment options in patients with a family history of aneurysm, or those with diagnosed aneurysm and/or aortic dissection, or those with other risk factors or conditions predisposing to aneurysm and/or aortic dissection (e.g., Marfan syndrome, Ehlers-Danlos vascular type, Takayasu arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, diagnosed atherosclerosis).
In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention at an emergency department.
Visual disturbances
If visual disturbances or other ocular effects occur, patients should seek immediate consultation with an ophthalmologist (see sections "Adverse reactions", "Ability to affect driving and use of machines").
Superinfection
With the use of levofloxacin, particularly prolonged use, opportunistic infections and overgrowth of resistant microorganisms may occur. If superinfection develops during therapy, appropriate measures should be taken.
Effect on laboratory tests
In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate results using more specific methods may be necessary. Levofloxacin inhibits the growth of Mycobacterium tuberculosis, so false-negative results may occur in bacteriological testing of patients with tuberculosis.
Use during pregnancy or breastfeeding
Pregnancy. Data on the use of levofloxacin in pregnant women are limited.
Due to the lack of human studies and the potential for quinolones to damage the joint cartilage in the growing organism, levofloxacin is contraindicated in pregnant women and in women who are breastfeeding. If pregnancy occurs during treatment, this should be reported to the physician.
Breastfeeding. Levofloxacin is contraindicated during breastfeeding. Information on the excretion of levofloxacin in breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage joint cartilage in the growing organism, levofloxacin should not be administered to women who are breastfeeding.
Fertility. Levofloxacin did not cause disorders of fertility or reproductive function in animals.
Ability to affect driving and use of machines
Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).
Dosage and Administration
The drug should be administered 1–2 times 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 normalization of body temperature or until microbiological tests confirm eradication of the causative agent.
Tablets should be swallowed whole with sufficient fluid. They may be taken with or without food.
The medicinal product should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only formulations containing buffering agents of aluminum or magnesium), and sucralfate (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Table 4
Use in adult patients with normal renal function (creatinine clearance exceeding 50 ml/min):
| Indications |
Daily dose |
Number of doses per day |
Duration of treatment |
| Acute bacterial sinusitis |
500 mg |
1 time |
10–14 days |
| Exacerbation of chronic obstructive pulmonary disease, including bronchitis |
500 mg |
1 time |
7–10 days |
| Community-acquired pneumonia |
500 mg |
1–2 times |
7–14 days |
| Acute pyelonephritis |
500 mg |
1 time |
7–10 days |
| Complicated urinary tract infections |
500 mg |
1 time |
7–14 days |
| Uncomplicated cystitis |
250 mg |
1 time |
3 days |
| Chronic bacterial prostatitis |
500 mg |
1 time |
28 days |
| Complicated skin and soft tissue infections |
500 mg |
1–2 times |
7–14 days |
| Pulmonary form of anthrax |
500 mg |
1 time |
8 weeks |
Table 5
Dosing for patients with impaired renal function in whom creatinine clearance is less than
50 mL/min.
| Creatinine clearance |
Dosing regimen (depending on severity of infection and nosological form) |
||
| 50–20 mL/min |
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 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 (as well as during 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 Additional doses are not required after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).
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, there is no need for dose adjustment.
Children.
The use of the drug is contraindicated in children under 18 years of age, as damage to the joint cartilage cannot be excluded.
Overdose.
The most important expected symptoms of overdose involve the central nervous system (dizziness, disturbance of consciousness, and seizures) and gastrointestinal reactions such as nausea and erosion of mucous membranes. According to study results, administration of doses higher than therapeutic ones has been associated with QT interval prolongation. In cases of overdose, careful patient monitoring, including ECG, is required.
Treatment: symptomatic therapy. In cases of acute overdose, gastric lavage is indicated. Antacid agents should be used to protect the gastric mucosa.
Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes available.
Adverse reactions.
The frequency of adverse reactions listed in Table 6 was determined using the following criteria: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).
Within each group, adverse reactions are listed in order of decreasing frequency.
Table 6
| System Organ Classes |
Common |
Uncommon |
Rare |
Unknown |
| Infections and infestations |
Fungal infections, including Candida species, overgrowth of resistant microorganisms, disruption of normal gastrointestinal flora, and development of secondary infections |
|||
| Endocrine system disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
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| Blood and lymphatic system disorders |
Leukopenia Eosinophilia |
Thrombocytopenia Neutropenia |
Pancytopenia Agranulocytosis Hemolytic anemia |
|
| Immune system disorders |
Angioedema Hypersensitivity (see section "Special warnings and precautions for use") |
Anaphylactic/anaphylactoid shock (see section "Special warnings and precautions for use") |
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| Metabolism and nutrition disorders |
Anorexia |
Hypoglycemia, mainly in diabetic patients (see section "Special warnings and precautions for use") |
Hyperglycemia Hypoglycemic coma (see section "Special warnings and precautions for use") |
|
| Psychiatric disorders* |
Insomnia |
Anxiety Restlessness Fear states Confusion Nervousness |
Psychotic reactions (including hallucinations, paranoia) Depression Agitation Unusual dreams Nightmares |
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 disturbances (parosmia), including anosmia (loss of smell) Dyskinesia (disturbance of motor coordination) Extrapyramidal disorders Ageusia Syncope (fainting) Benign intracranial hypertension |
| Eye disorders* |
Visual disturbances such as blurred vision, unsharp vision (see section "Special warnings and precautions for use") |
Transient loss of vision (see section "Special warnings and precautions for use), 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 and torsade de pointes (mainly in patients with risk factors for QT interval prolongation) QT interval prolongation on electrocardiogram (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 system disorders |
Dyspnea (shortness of breath) |
Bronchospasm Allergic pneumonia |
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| Gastrointestinal disorders |
Diarrhea Vomiting Nausea |
Abdominal pain Dyspepsia Flatulence/distension Constipation |
Hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use") Pancreatitis |
|
| Hepatobiliary disorders |
Elevated liver enzyme levels (ALT/AST, alkaline phosphatase, GGT) |
Elevated blood bilirubin levels |
Jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), mainly in patients with serious underlying diseases (see section "Special warnings and precautions for use") Hepatitis |
|
| Skin and subcutaneous tissue disorders |
Rash Pruritus Urticaria Hyperhidrosis |
Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), localized skin reactions due to drugs |
Toxic epidermal necrolysis (Lyell's syndrome) Stevens-Johnson syndrome Multiform erythema Photosensitivity reactions (see section "Special warnings and precautions for use") Leukocytoclastic vasculitis Stomatitis |
|
| Musculoskeletal and connective tissue disorders* |
Arthralgia Myalgia |
Tendon disorders (see sections "Contraindications", "Special warnings and precautions for use"), including 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 |
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| Renal and urinary system disorders |
Elevated serum creatinine levels |
Acute renal failure (e.g., due to interstitial nephritis) |
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| General disorders* |
Asthenia |
Increased body temperature (pyrexia) |
Pain (including back, chest, and limb pain) |
a Anaphylactic and anaphylactoid reactions, which may sometimes occur even after administration of the first dose.
b Skin and mucous membrane reactions, which may sometimes occur even after administration of the first dose.
* With the use of quinolones and fluoroquinolones, very rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse drug reactions have been reported, sometimes affecting multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disorder, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste and smell), in some cases regardless of the presence of risk factors (see section "Special precautions").
Among other adverse effects associated with fluoroquinolone intake, attacks of porphyria in patients with existing porphyria.
Shelf life.
3 years.
Storage conditions.
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
5 or 10 tablets in a blister pack. 1 blister pack in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Simpex Pharma Pvt. Ltd.
Manufacturer's address and location of operations.
Office: B-4/160, Safdarjung Enclave, New Delhi – 110 029, India.
Production site: C7 to C13 and C59 to C64, Siggadi Development Center (SIDCUL), Siggadi, Kotdwar – 246149, Dist. Pauri Garhwal, Uttarakhand, India.