Floxium
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLOXIUM® (FLOXIUM)
Composition:
Active substance: levofloxacin;
100 ml of solution contain levofloxacin hemihydrate – 512.46 mg, equivalent to levofloxacin – 500.0 mg;
Excipients: sodium chloride; sodium hydroxide; hydrochloric acid concentrated; water for injections.
Pharmaceutical form. Infusion solution.
Main physico-chemical properties: clear solution, yellow to greenish-yellow in color.
Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.
ATC code J01MA12.
Pharmacological properties.
Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group,
S-enantiomer of the racemic mixture of the drug ofloxacin.
Mechanism of action. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.
Pharmacokinetic/pharmacodynamic relationship. The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC).
Mechanism of resistance
Resistance to levofloxacin develops through a stepwise process of mutations in the target site of both types of topoisomerase II, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as restricted penetration (common in Pseudomonas) and efflux mechanisms, may also affect susceptibility to levofloxacin.
Cross-resistance has been established between levofloxacin and other fluoroquinolones.
Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.
Breakpoints
The recommended breakpoints for minimum inhibitory concentration (MIC) of levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant) and microorganisms with intermediate susceptibility from resistant microorganisms, 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 |
| S. pneumoniae1 |
≤ 2 mg/L |
> 2 mg/L |
| Streptococcus A, B, C, G |
≤ 1 mg/L |
> 2 mg/L |
| H. influenzae2,3 |
≤ 1 mg/L |
> 1 mg/L |
| M. catarrhalis3 |
≤ 1 mg/L |
> 1 mg/L |
| Intermediate values, not species-related4 |
≤ 1 mg/L |
> 2 mg/L |
|
||
The prevalence of resistance may vary geographically and over time for individual species, and it is advisable to obtain local information on microbial resistance, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the benefit of the drug at least questionable for certain types of infections.
Antibacterial spectrum
Typically sensitive 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 for which acquired (secondary) resistance may be problematic
Aerobic gram-positive bacteria
Enterococcus faecalis, Staphylococcus aureus methicillin-resistant**, coagulase-negative Staphylococcus haemolyticus.
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 cross-resistance to fluoroquinolones, including levofloxacin.
Pharmacokinetics.
Absorption
When administered orally, levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations are reached within 1–2 hours after administration. Absolute bioavailability is approximately 99–100%. Steady-state levels are achieved within 48 hours with dosing regimens 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 a single 500 mg dose and after repeated doses, indicating extensive distribution into body tissues.
Penetration into tissues and body fluids
Levofloxacin has demonstrated penetration into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, lung parenchyma, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.
Biotransformation
Levofloxacin undergoes minimal metabolism. Metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). It is primarily excreted by the kidneys (over 85% of the administered dose).
Linearity
Levofloxacin follows linear pharmacokinetics in the range of 50–1000 mg.
Patients with renal impairment
The pharmacokinetics of levofloxacin are affected by the degree of renal impairment. With reduced kidney function, renal excretion and clearance decrease, and elimination half-lives increase, as shown in Table 2.
Table 2
Pharmacokinetics in renal impairment after a single 500 mg dose of levofloxacin
| Creatinine clearance (ml/min) |
< 20 |
20–49 |
50–80 |
| Renal clearance (ml/min) |
13 |
26 |
57 |
| Elimination half-life (hours) |
35 |
27 |
9 |
Geriatric patients
There are no significant differences in the pharmacokinetics of levofloxacin in younger and elderly patients, except for differences related to creatinine clearance.
Gender differences
Separate analysis in male and female patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.
Clinical characteristics.
Indications.
Floxium®, infusion solution, is indicated for the treatment of the following infectious diseases in adults:
- Community-acquired pneumonia.
- Complicated skin and soft tissue infections.
For the above-mentioned infectious diseases, levofloxacin should be prescribed only when other antibacterial agents primarily used for initial treatment of these infections are insufficiently effective.
- Acute pyelonephritis and complicated urinary tract infections.
- Chronic bacterial prostatitis.
- Pulmonary form of anthrax: post-exposure prophylaxis and definitive treatment.
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications.
Floxium®, infusion solution, must not be administered in the following cases:
- Hypersensitivity to the active pharmaceutical ingredient, to other quinolones, or to any other component of the medicinal product;
- Epilepsy;
- Tendon disorders following fluoroquinolone administration;
- Children and adolescents;
- Pregnancy;
- Breastfeeding.
Special safety precautions.
For single use only. Discard unused solution.
Before administration, the medicinal product should be visually inspected for particulate matter and discoloration. Only clear greenish-yellow solution free of visible particles should be used. Levofloxacin infusion solution should be used immediately (within 3 hours) after perforation of the rubber stopper to prevent any bacterial contamination. Protection from light during infusion is not required.
This medicinal product may be administered separately or with the following solutions: 0.9% sodium chloride solution, 5% dextrose injection, 2.5% dextrose in Ringer's solution, multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes). Chemical and physical compatibility of levofloxacin infusion solution with the above-mentioned solutions has been demonstrated for 4 hours under room conditions.
For information on incompatibility, see section "Incompatibility".
The shelf-life of the vial after removal from the outer packaging is 3 days (under room lighting conditions).
From a microbiological point of view, after first opening the medicinal product should be used immediately. If not used immediately, responsibility for storage conditions and duration of use lies with the user.
Any unused medicinal product or waste material must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other types of interactions.
Effect of other medicinal products on levofloxacin
Theophylline, fenbufen or similar non-steroidal anti-inflammatory medicinal products
No pharmacokinetic interaction between levofloxacin and theophylline was observed in clinical studies. However, a significant reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. The concentration of levofloxacin was approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.
Probenecid and cimetidine
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin decreases 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, statistically significant kinetic differences are unlikely to have clinical significance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.
Other information
Clinical pharmacological studies have shown that no clinically significant effect on the pharmacokinetics of levofloxacin occurs when levofloxacin is taken with calcium carbonate, digoxin, glyburide, or ranitidine.
Effect of levofloxacin on other medicinal products
Cyclosporine
The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.
Vitamin K antagonists
When used 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 concomitant vitamin K antagonists 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, neuroleptics) (see section "Special precautions for use" (QT interval prolongation)).
Special precautions for use.
Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to agents containing quinolones or fluoroquinolones. Levofloxacin should be prescribed to such patients only if no alternative treatment options are available and after careful benefit/risk assessment.
Prolonged, disabling, and potentially irreversible serious adverse reactions
Very rarely, in patients receiving quinolones or fluoroquinolones, prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various organ systems (particularly musculoskeletal, nervous, psychiatric, and sensory organs) have been reported, regardless of age or presence of risk factors. Treatment should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.
Aneurysm and dissection of the aorta, and heart valve regurgitation/insufficiency
Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as regurgitation of the aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart 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 defects, or in patients with an existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:
- for both aortic aneurysm and dissection, and heart valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis), or additionally
- for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or additionally
- for heart valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection, and rupture may be increased in patients concurrently receiving systemic corticosteroids.
Patients should seek immediate medical attention at an emergency department if they experience sudden abdominal, chest, or back pain. Patients should be advised to seek immediate medical help if they develop acute shortness of breath, a new episode of palpitations, or develop abdominal or lower limb swelling.
Duration of infusion
The recommended duration of infusion is at least 30 minutes for the 250 mg infusion solution and 60 minutes for the 500 mg infusion solution of Floxium®. With ofloxacin, tachycardia and transient lowering of blood pressure have been observed during infusion. In rare cases, this may lead to a sudden drop in blood pressure or circulatory collapse. If a marked decrease in blood pressure occurs during levofloxacin (*l-*isomer of ofloxacin) infusion, the infusion should be stopped immediately.
Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin-resistant Staphylococcus aureus (MRSA) is very likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory testing confirms susceptibility to levofloxacin (see section "Pharmacodynamics").
Resistance of E. coli, the most common pathogen causing urinary tract infections, to fluoroquinolones varies across different regions. Physicians should consider local prevalence of E. coli resistance to fluoroquinolones when prescribing levofloxacin.
Pulmonary form of anthrax: clinical practice is based on in vitro susceptibility data for Bacillus anthracis, experimental animal studies, and limited human data. Physicians should refer to established national and/or international guidelines for the treatment of anthrax.
Tendinitis and tendon rupture
Tendinitis and tendon rupture (particularly of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or 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 renal impairment, transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.
If signs of tendinitis occur (e.g., painful swelling, inflammation), treatment 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 develop.
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 levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately at the first sign of myoclonus, and appropriate treatment initiated.
Blood disorders
Treatment with levofloxacin may lead to bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse reactions"). If any of these disorders are suspected, blood counts should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.
Clostridium difficile-associated disease
Diarrhea, especially severe, persistent, and/or hemorrhagic, occurring during or after treatment with levofloxacin (sometimes weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD ranges from mild to life-threatening. The most severe form is pseudomembranous colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated. Antiperistaltic agents 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 and should be used with extreme caution in patients predisposed to seizures, such as those with prior central nervous system disorders or those receiving concomitant medications that lower the cerebral seizure threshold (e.g., theophylline) (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin treatment should be discontinued.
Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
Patients with latent or manifest G6PD enzyme deficiency may be susceptible to hemolytic reactions when treated with quinolone antibacterial agents. Therefore, levofloxacin should be used with caution in such patients, and the risk of hemolysis should be closely monitored.
Patients with renal impairment
Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with renal impairment (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 or emergency assistance for appropriate emergency measures.
Severe skin reactions
Severe skin reactions, including toxic epidermal necrolysis (TEN, also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with levofloxacin use, which may be fatal. Before initiating treatment, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, levofloxacin treatment should be discontinued immediately and alternative therapy considered. Patients who have experienced SJS, TEN, or DRESS with levofloxacin should never be re-exposed to levofloxacin.
Blood glucose fluctuations
As with other quinolones, fluctuations in blood glucose levels, including hyperglycemia and hypoglycemia, have been reported, particularly in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").
Phototoxicity prevention
Although phototoxicity is very rare with levofloxacin, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps or tanning beds) during treatment and for 48 hours after discontinuation of treatment.
Patients receiving vitamin K antagonists
Due to the potential for increased coagulation test parameters (PT/INR) and/or bleeding in patients receiving Floxium® in combination with a vitamin K antagonist (e.g., warfarin), coagulation tests should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").
Psychotic reactions. Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts 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 symptomatic therapy initiated. Levofloxacin should be used cautiously 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, neuroleptics);
- uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
- advanced age and female gender — these patients may have increased sensitivity to QT-prolonging drugs;
- cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness has been reported in patients receiving fluoroquinolones, including levofloxacin. If patients experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, levofloxacin should be discontinued and medical advice sought to prevent irreversible damage.
Opioids
In patients receiving levofloxacin, urine testing for opioids may yield false-positive results. Confirmation of positive opioid results using more specific methods may be necessary.
Hepatobiliary disorders
Cases of necrotizing 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 consult a physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, can cause neuromuscular blockade and exacerbate 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 treated with fluoroquinolones. Levofloxacin is not recommended for patients with a history of myasthenia gravis.
Visual disturbances
If vision is impaired or any ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Adverse reactions" and "Effect on ability to drive and use machines").
Superinfection
Prolonged use of levofloxacin may lead to overgrowth of microorganisms not susceptible to the drug. Appropriate measures should be taken if superinfection occurs during therapy.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.
This medicinal product contains 371 mg of sodium per 100 mL of solution. Caution is advised when administering to patients on a sodium-restricted diet.
This should be considered for patients on sodium-controlled diets and in situations where water intake must be limited.
Store without outer packaging for up to 3 days under room light conditions.
After first perforation of the stopper, the solution should be used immediately.
Use during pregnancy or breastfeeding.
Pregnancy.
Data on the use of levofloxacin during pregnancy are limited. Animal studies do not indicate direct or indirect harmful effects with regard to reproductive toxicity. However, due to the lack of human data and experimental evidence indicating a risk of cartilage damage in the growing organism by fluoroquinolones, levofloxacin should not be administered to pregnant women (see section "Contraindications").
Breastfeeding.
Levofloxacin is contraindicated in breastfeeding women. There is insufficient information on the excretion of levofloxacin in breast milk, although other fluoroquinolones are known to pass into breast milk. Due to the lack of human data and experimental evidence indicating a risk of cartilage damage in the growing organism by fluoroquinolones, levofloxacin should not be administered to breastfeeding women (see section "Contraindications").
Fertility .
Levofloxacin does not impair fertility or reproductive function in rats.
Effect on ability to drive and use machines.
Some adverse effects (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and react, and therefore may pose a risk in situations where such abilities are particularly important (e.g., driving a car or operating machinery).
Method of Administration and Dosage
Levofloxacin for infusion solution should be administered slowly by intravenous infusion once or twice daily. The dosage depends on the type and severity of the infection, as well as the susceptibility of the likely causative organism. It is possible to switch from initial intravenous administration of levofloxacin to the appropriate oral dosage form according to the instructions for medical use of the drug in the form of film-coated tablets, depending on the patient's condition. Due to the bioequivalence of oral and parenteral forms, the dosage may be the same.
Administration Method
The following dosages are recommended for administration of levofloxacin:
Table 3
Dosage for patients with normal renal function (creatinine clearance > 50 mL/min)
| Indications |
Daily dose frequency (according to severity) |
Total duration of treatment1 |
| Community-acquired pneumonia |
500 mg once or twice daily |
7–14 days |
| Acute pyelonephritis |
500 mg once daily |
7–10 days |
| Complicated urinary tract infections |
500 mg once daily |
7–14 days |
| Chronic bacterial prostatitis |
500 mg once daily |
28 days |
| Complicated skin and soft tissue infections |
500 mg once or twice daily |
7–14 days |
| Pulmonary form of anthrax |
500 mg once daily |
8 weeks |
1The duration of treatment includes both intravenous and oral administration. The time to switch from intravenous to oral administration depends on the clinical condition, but usually takes from 2 to 4 days.
Table 4
Dosage for adult patients with impaired renal function in whom creatinine clearance is ≤ 50 ml/min
| Dosing regimen |
|||
| 250 mg/24 hours |
500 mg/24 hours |
500 mg/12 hours |
|
| Creatinine clearance |
initial dose: 250 mg |
initial dose: 500 mg |
initial dose: 500 mg |
| 50–20 mL/min |
then: 125 mg/24 hours |
then: 250 mg/24 hours |
then: 250 mg/12 hours |
| 19–10 mL/min |
then: 125 mg/48 hours |
then: 125 mg/24 hours |
then: 125 mg/12 hours |
| <10 mL/min (including hemodialysis and CAPD)1 |
then: 125 mg/48 hours |
then: 125 mg/24 hours |
then: 125 mg/24 hours |
1After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.
Dosing in patients with hepatic impairment.
Dose adjustment is not required, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.
Dosing in elderly patients.
If renal function is not impaired, dose adjustment is not necessary in elderly patients (see section "Special precautions").
Route of administration
Floxium®, infusion solution, is intended for slow intravenous infusion only. The solution should be administered once or twice daily. The infusion time for Floxium® should be at least 30 minutes for the 250 mg dose or 60 minutes for the 500 mg dose (see also section "Special precautions").
For information on incompatibility of Floxium® with other infusion solutions, see section "Incompatibility", and for compatibility, see section "Special safety precautions".
Children.
The use of the drug is contraindicated in children, as damage to joint cartilage cannot be excluded.
Overdose.
According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic ones, the most serious signs expected after acute overdose of levofloxacin infusion solution are symptoms related to the central nervous system (CNS), such as confusion, dizziness, disturbances of consciousness, seizures, myoclonus, and QT interval prolongation.
During post-marketing surveillance, the following CNS adverse reactions have been observed: confusion, convulsions, hallucinations, and tremor.
Treatment. In cases of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), is not effective in removing levofloxacin from the body. There are no specific antidotes.
Adverse Reactions
The frequency of adverse effects was determined according to the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (≥1/10000), frequency not known (cannot be estimated from available data).
Infections and infestations:
Uncommon: fungal infections, including infections caused by Candida species, overgrowth of other resistant microorganisms.
Blood and lymphatic system disorders:
Uncommon: leukopenia, eosinophilia;
Rare: thrombocytopenia, neutropenia;
Frequency not known: bone marrow depression, including aplastic anemia, agranulocytosis, pancytopenia, hemolytic anemia.
Immune system disorders:
Rare: angioedema, hypersensitivity;
Frequency not known: anaphylactic shock, anaphylactoid shock.
Anaphylactic and anaphylactoid reactions may occasionally occur even after administration of the first dose.
Metabolism and nutrition disorders:
Uncommon: anorexia;
Rare: hypoglycemia, especially in patients with diabetes;
Frequency not known: hyperglycemia, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, excessive sweating, and tremor of extremities. Syndrome of inappropriate antidiuretic hormone secretion (SIADH, rarely observed).
Psychiatric disorders:
Common: insomnia;
Uncommon: nervousness, confusion, anxiety;
Rare: psychotic disorders (including hallucinations, paranoia), depression, agitation, unusual dreams, nightmares;
Frequency not known: mania, psychotic reactions with self-destructive behavior, including suicidal ideation or actions.
Nervous system disorders*:
Common: headache, dizziness;
Uncommon: somnolence, tremor, dysgeusia (subjective taste disturbance);
Rare: convulsions, paresthesia;
Frequency not known: myoclonus, sensory or sensorimotor peripheral neuropathy, parosmia (disturbance of smell), including anosmia (loss of smell), dyskinesia, extrapyramidal disorders, ageusia (loss of taste), syncope, benign intracranial hypertension.
Eye disorders*:
Rare: visual disturbances such as blurred vision, visual blurring;
Frequency not known: transient loss of vision.
Cases of retinal detachment have been reported (see section "Special Warnings and Precautions for Use").
Ear and labyrinth disorders*:
Uncommon: vertigo;
Rare: hearing disturbances;
Frequency not known: hearing impairment, hearing loss.
Cardiac disorders**:
Rare: tachycardia, palpitations;
Frequency not known: ventricular tachycardia, which may lead to cardiac arrest, including torsade de pointes; these have been observed primarily in patients with risk factors for QT interval prolongation, QT interval prolongation on electrocardiogram (see sections "Special Warnings and Precautions for Use" (QT Prolongation) and "Overdose").
Vascular disorders**:
Common: phlebitis;
Rare: hypotension.
Respiratory system disorders:
Uncommon: dyspnea;
Frequency not known: bronchospasm, allergic pneumonia.
Gastrointestinal disorders:
Common: diarrhea, nausea, vomiting;
Uncommon: abdominal pain, dyspepsia, bloating, constipation;
Frequency not known: hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis, pancreatitis.
Hepatobiliary disorders:
Common: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT);
Uncommon: increased blood bilirubin;
Frequency not known: jaundice and severe liver injury, including cases of acute liver failure (sometimes fatal), predominantly in patients with severe underlying diseases, hepatitis.
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus, urticaria, hyperhidrosis;
Frequency not known: skin hyperpigmentation, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS, rarely observed), localized skin rash caused by drugs (see section "Special Warnings and Precautions for Use"), exudative polymorphic erythema, photosensitivity reactions, leukocytoclastic vasculitis, stomatitis.
Skin and mucous membrane reactions may occasionally occur even after administration of the first dose.
Musculoskeletal and connective tissue disorders*:
Uncommon: arthralgia, myalgia;
Rare: tendon disorders, including inflammation (tendinitis, e.g., of Achilles tendon), muscle weakness, which may be particularly significant in patients with severe myasthenia gravis;
Frequency not known: rhabdomyolysis, tendon rupture (e.g., Achilles tendon), ligament rupture, muscle rupture, arthritis.
Renal and urinary disorders:
Uncommon: elevated serum creatinine levels;
Rare: acute renal failure (e.g., due to interstitial nephritis).
General disorders*:
Common: infusion site reactions (pain, redness);
Uncommon: asthenia;
Rare: increased body temperature (pyrexia);
Frequency not known: pain (including back, chest, and limb pain).
Among other adverse effects associated with fluoroquinolone use, attacks of porphyria have been reported in patients with existing porphyria.
* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, have experienced prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting multiple organ systems (including tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disorders).
** In patients receiving fluoroquinolones, cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/incompetence of any cardiac valve have been reported (see section "Special Warnings and Precautions for Use").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua
Shelf life. 3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 ºC.
Keep out of reach and sight of children.
Incompatibilities.
Floxium® infusion solution must not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate). For a list of solutions compatible with the product, see section "Special Precautions for Safety".
Packaging. 100 ml in a bottle; 1 bottle per carton.
Prescription status. Prescription only.
Manufacturer.
JSC "Halychfarm", Ukraine.
Manufacturer's address.
JSC "Halychfarm", Ukraine, 79024, Lviv, Opryshkivska St., 6/8.
Marketing Authorization Holder. JSC "Kyivmedpreparat", Ukraine.
Address of Marketing Authorization Holder. Ukraine, 01032, Kyiv, Saksaganskoho St., 139.