Levofloxacin-teva
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN-TEVA (LEVOfloxacin-Teva)
Composition:
Active substance: levofloxacin;
One film-coated tablet contains levofloxacin hemihydrate 256.23 mg, equivalent to levofloxacin 250 mg, or levofloxacin hemihydrate 512.46 mg, equivalent to levofloxacin 500 mg;
Excipients:
Core: sodium stearyl fumarate, crospovidone, colloidal anhydrous silicon dioxide, copovidone, microcrystalline cellulose;
Film coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide red (E 172), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: pink, oval, biconvex film-coated tablets, 6 x 13 mm or 8 x 16 mm in size, with a score line on one side and along the edges; engraved with the letter "L" on the side without the score line.
Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.
ATC code J01M A12.
Pharmacological properties.
Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group and the S-(-) enantiomer of the racemic mixture of the drug ofloxacin.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA gyrase and topoisomerase IV complex.
Pharmacokinetic/pharmacodynamic relationship
The extent of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC).
Mechanism of resistance development
Resistance to levofloxacin develops gradually due to mutations in the target site of type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as penetration barriers (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.
Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.
Clinical breakpoints
The recommended EUCAST (European Committee on Antimicrobial Susceptibility Testing) MIC breakpoints for levofloxacin, used to differentiate susceptible microorganisms from those with intermediate susceptibility and resistant microorganisms, are presented in the table below for MIC testing (mg/l).
Table 1
EUCAST clinically defined MIC breakpoints for levofloxacin (version 2.0, 2012-01-01)
| Organism |
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. pneumoniae 1 |
≤ 2 mg/l |
> 2 mg/l |
| Streptococcus A, B, C, G |
≤ 1 mg/l |
> 2 mg/l |
| H. influenzae 2, 3 |
≤ 1 mg/l |
> 1 mg/l |
| M. catarrhalis 3 |
≤ 1 mg/l |
> 1 mg/l |
| Clinical breakpoints, not species-specific 4 |
≤ 1 mg/l |
> 2 mg/l |
|
||
The prevalence of resistance in individual species may vary geographically and over time, so local information on resistance is very important, especially when treating severe infections. Expert advice should be sought when local resistance prevalence raises doubts about the appropriateness of using the medicinal product, at least for certain types of infections.
Generally susceptible species
Aerobic Gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-sensitive, Staphylococcus saprophyticus, Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.
Aerobic Gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, 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 with possible acquired resistance
Aerobic Gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant (highly likely to have co-resistance to fluoroquinolones, including levofloxacin), coagulase-negative Staphylococcus spp.
Aerobic Gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.
Anaerobic bacteria: Bacteroides fragilis.
Naturally resistant strains
Aerobic Gram-positive bacteria: Enterococcus faecium.
Pharmacokinetics.
Absorption. When administered orally, levofloxacin is rapidly and almost completely absorbed; maximum plasma concentration (Cmax) is reached within 1–2 hours after administration. Absolute bioavailability is 99–100%. Food intake slightly affects its absorption. Steady-state levels are achieved within 48 hours after administration of 500 mg once or twice daily.
Distribution. Approximately 30–40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after both single and repeated 500 mg doses, indicating extensive distribution into body tissues.
Penetration into tissues and body fluids. It has been demonstrated that levofloxacin penetrates into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle fluid), prostate tissue, and urine. However, penetration of levofloxacin into cerebrospinal fluid is poor.
Metabolism. Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. The levofloxacin molecule is stereochemically stable and does not undergo chiral inversion.
Elimination. After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). Mean apparent total clearance of levofloxacin after a single 500 mg dose is 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating interchangeability of these routes.
Linearity. Levofloxacin exhibits linear pharmacokinetics in the dose range of 50 to 1000 mg.
Patients with renal impairment. Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, renal elimination and creatinine clearance decrease, and elimination half-life increases (see Table 2).
Table 2
Pharmacokinetics in renal impairment
after a single oral dose of 500 mg
| Clcr [mL/min] |
< 20 |
20–49 |
50–80 |
| ClR [mL/min] |
13 |
26 |
57 |
| t1/2 [hours] |
35 |
27 |
9 |
Geriatric patients. There are no significant differences in the pharmacokinetics of levofloxacin in younger patients and geriatric patients, except for differences related to creatinine clearance.
Gender. Separate analysis of male and female patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these differences are clinically significant.
Clinical characteristics.
Indications.
Levofloxacin-Teva 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.
Levofloxacin-Teva should be used for the treatment of the above-mentioned infections only when other antibacterial agents, typically used for initial treatment of these infections, cannot be used.
- complicated urinary tract infections and acute pyelonephritis;
- chronic bacterial prostatitis;
- pulmonary form of anthrax: post-exposure prophylaxis and treatment.
Levofloxacin-Teva in this pharmaceutical form (film-coated tablets) may be used to complete the course of therapy in patients who have shown clinical improvement during initial treatment with levofloxacin intravenous solution.
Official recommendations on 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 disorders related to the use of fluoroquinolones.
Paediatric age.
Pregnancy and lactation.
Interaction with other medicinal products and other forms of interaction.
Effect of other medicinal products on levofloxacin
Iron salts, zinc salts, antacids containing magnesium and aluminium, didanosine
The absorption of levofloxacin is significantly reduced when iron salts, magnesium- or aluminium-containing antacids, or didanosine (only formulations containing aluminium or magnesium buffering agents) are administered concomitantly with levofloxacin tablets. Concomitant administration of fluoroquinolones with multivitamin preparations containing zinc results in reduced oral absorption. Medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (this applies only to medicinal forms of didanosine containing aluminium or magnesium buffering agents) should not be administered within 2 hours before or after the intake of levofloxacin tablets (see section "Dosage and administration").
Calcium salts have minimal effect on the absorption of levofloxacin following oral administration.
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 at least 2 hours after the intake of levofloxacin tablets.
Theophylline, fenbufen, or similar non-steroidal anti-inflammatory drugs (NSAIDs)
No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs, or other agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher when administered with fenbufen compared to levofloxacin 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% with probenecid. This is explained by the fact that both drugs can inhibit tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that these statistically significant kinetic differences will have clinical relevance. Levofloxacin should be administered with caution together with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.
Other medicinal products
No clinically significant effect on the pharmacokinetics of levofloxacin has been observed when levofloxacin is used concomitantly 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 parameters (prothrombin time [PT]/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, as well as other fluoroquinolones, should be used with caution in patients receiving medicinal products capable of prolonging the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) (see section "Special warnings and precautions for use. QT interval prolongation").
Other important information
No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.
Other forms of interaction
Corticosteroids
The risk of tendinitis and tendon rupture is increased in patients receiving concomitant corticosteroid therapy and levofloxacin. Therefore, concomitant administration of corticosteroids with levofloxacin should be avoided.
Food intake
No clinically significant interaction with food has been observed; therefore, Levofloxacin-Teva tablets may be taken independently of food intake.
Special precautions for use.
Levofloxacin should not be used in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").
Methicillin-resistant S. aureus
There is a very high likelihood of co-resistance of methicillin-resistant S. aureus (MRSA) to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and if use of the 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 appropriately diagnosed.
Resistance of E. coli (the most common pathogen in urinary tract infections) to fluoroquinolones varies across different countries. Local prevalence of E. coli resistance to fluoroquinolones should be taken into account when prescribing fluoroquinolones.
For pulmonary anthrax, use of the medicinal product is based on in vitro susceptibility data for Bacillus anthracis, experimental animal data, and limited human use data. Physicians should refer to national and/or international guidelines for the treatment of anthrax.
Prolonged, disabling, and potentially irreversible serious adverse reactions
Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous systems, psyche, sensory organs) have been observed in patients treated with quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin therapy must be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.
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 and fluoroquinolones; cases have been reported even several months after discontinuation of therapy. 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 therapy with corticosteroids should be avoided.
If initial symptoms of tendinitis (e.g., painful swelling, inflammation) occur, levofloxacin treatment should be discontinued and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear.
The daily dose should be adjusted in elderly patients based on creatinine clearance. Elderly patients receiving levofloxacin should be closely monitored.
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 impaired renal function if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, 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 (see section "Adverse Reactions"). 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 promptly. Medicinal products that inhibit intestinal peristalsis are contraindicated in this clinical situation.
Patients predisposed to seizures
Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, the medicinal product Levofloxacin-Teva should be used with extreme caution in patients predisposed to seizures and in patients receiving drugs that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs, 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 prone to hemolytic reactions when treated with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in such patients, and they should be monitored for possible hemolysis.
Patients with renal impairment
Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and administration").
Hypersensitivity reactions
Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock), in some cases after administration of the first dose (see section "Adverse Reactions"). Patients should discontinue treatment immediately and seek medical advice or emergency medical assistance.
Severe skin reactions
Severe skin reactions, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during treatment with levofloxacin. These reactions may be life-threatening or fatal (see section "Adverse Reactions"). Patients should be informed about the signs and symptoms of these severe skin reactions, and close monitoring should be maintained. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-initiation of levofloxacin therapy is prohibited in patients who have experienced a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during treatment with levofloxacin.
Blood glucose alterations
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 (see section "Adverse Reactions"). Cases of hypoglycemic coma have been documented. Blood glucose levels should be monitored in diabetic patients. If blood glucose changes 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, patients are advised to avoid intense sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) during treatment and for 48 hours after its discontinuation to prevent its development.
Patients receiving vitamin K antagonists
Due to the possible increase in coagulation test parameters (PT/INR) and/or bleeding in patients taking levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation parameters should be monitored when these medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").
Psychotic reactions
Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these 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. Caution is recommended when prescribing Levofloxacin-Teva to 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:
- congenital QT prolongation syndrome;
- concomitant use of medicinal products capable of prolonging the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
- uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
- cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia).
Elderly patients and women may be more sensitive to medicinal products that prolong the QTc interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration. Elderly patients", "Overdose", and "Adverse Reactions").
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients taking quinolones and fluoroquinolones. To prevent the development of potentially irreversible conditions, patients receiving levofloxacin who experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness should inform their physician before continuing treatment (see section "Adverse Reactions").
Hepatobiliary disorders
Cases of liver necrosis up to liver failure with fatal outcome have been reported with levofloxacin use (mainly in patients with severe underlying conditions, e.g., sepsis) (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs 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 exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported in patients with myasthenia gravis during post-marketing use of fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.
Visual disturbances
If visual disturbances or other effects on the visual organs occur, an ophthalmologist should be consulted immediately (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse Reactions").
Superinfection
With the use of levofloxacin, particularly prolonged use, overgrowth of microorganisms resistant to the drug may occur. If superinfection develops during therapy, appropriate measures should be taken.
Aortic aneurysm and dissection, cardiac valve regurgitation/insufficiency
Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and of regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse Reactions"). Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a family history of aneurysm or congenital heart valve defect, or in patients with diagnosed aneurysm and/or aortic dissection, or with heart valve disease, or in the presence of other risk factors or predisposing conditions:
- for both aortic aneurysm and dissection and cardiac 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, diagnosed 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.
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 experience acute shortness of breath, a new episode of palpitations, or development of abdominal or lower limb edema.
Effect on laboratory tests
In patients taking levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.
Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative bacteriological test results in patients with tuberculosis.
Blood disorders
During treatment with levofloxacin, bone marrow toxicity may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse Reactions"). If any of these blood disorders are suspected, blood parameters should be monitored. If test results deviate from normal, discontinuation of levofloxacin therapy should be considered.
Excipients
The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
The sodium content of one tablet of this medicinal product is less than 1 mmol (23 mg), i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy. Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects related to reproductive toxicity.
Due to the lack of human studies and the potential for quinolones to damage the articular cartilage in a growing organism, levofloxacin is contraindicated in pregnant women and in women who are breastfeeding. If pregnancy occurs during treatment, the physician should be informed.
Breastfeeding. Levofloxacin is contraindicated during breastfeeding. Information on the excretion of levofloxacin into breast milk is insufficient, although other fluoroquinolones are excreted into breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage articular cartilage in a growing organism, the medicinal product Levofloxacin-Teva must not be administered to women who are breastfeeding.
Fertility. Levofloxacin did not cause fertility or reproductive function disorders in rats.
Ability to influence reaction rate when driving or operating machinery.
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 vehicle or operating machinery).
Method of administration and dosage
Levofloxacin-Teva tablets are taken once or twice daily. The dose depends on the type, severity of infection, and sensitivity of the probable causative agent.
Levofloxacin-Teva in this pharmaceutical form (film-coated tablets) may be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin infusion solution, using the same dosage regimen, considering the bioequivalence of the parenteral and oral dosage forms.
Levofloxacin-Teva tablets should be swallowed whole, without chewing, with sufficient fluid. For convenience in dosing, the tablet may be divided along the break line. Tablets may be taken regardless of food intake.
The medicinal product should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine (only for formulations containing aluminium or magnesium in buffering agents), and sucralfate (see section "Interaction with other medicinal products and other forms of interaction").
Table 3
Recommended dosage for adult patients with normal renal function
(creatinine clearance >50 mL/min)
| Indications |
Daily dose (depending on severity) |
Number of doses per day |
Treatment duration (depending on severity) |
| Acute bacterial sinusitis |
500 mg |
Once |
10–14 days |
| Exacerbation of chronic obstructive pulmonary disease of bacterial origin, including bronchitis |
500 mg |
Once |
7–10 days |
| Community-acquired pneumonia |
500 mg |
1–2 times |
7–14 days |
| Acute pyelonephritis |
500 mg |
Once |
7–10 days |
| Complicated urinary tract infections |
500 mg |
Once |
7–14 days |
| Uncomplicated cystitis |
250 mg |
Once |
3 days |
| Chronic bacterial prostatitis |
500 mg |
Once |
28 days |
| Complicated skin and soft tissue infections |
500 mg |
1–2 times |
7–14 days |
| Pulmonary form of anthrax |
500 mg |
Once |
8 weeks |
Special populations
Table 4
Dosing for patients with impaired renal function (creatinine clearance ≤ 50 ml/min)
| Dosing regimen (depending on infection severity and nosological form) |
|||
| 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 |
subsequent – 125 mg/24 hours |
subsequent – 250 mg/24 hours |
subsequent – 250 mg/12 hours |
| 19–10 mL/min |
subsequent – 125 mg/48 hours |
subsequent – 125 mg/24 hours |
subsequent – 125 mg/12 hours |
| < 10 mL/min (as well as during hemodialysis and CRRT1) |
subsequent – 125 mg/48 hours |
subsequent – 125 mg/24 hours |
subsequent – 125 mg/24 hours |
1 Additional doses are not required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.
Elderly patients. If renal function is not impaired, dose adjustment is not required (see section "Special warnings and precautions for use": tendinitis and tendon rupture, QT interval prolongation).
Children. Levofloxacin-Teva is contraindicated in children, as damage to joint cartilage cannot be excluded (see section "Contraindications").
Overdose.
Symptoms. Based on animal toxicity studies and clinical pharmacological investigations conducted with doses higher than therapeutic ones, the most significant signs expected after acute levofloxacin overdose include central nervous system (CNS) effects (confusion, dizziness, altered consciousness, and convulsions); QT interval prolongation is possible; gastrointestinal reactions such as nausea and mucosal erosions may occur.
In the post-marketing period, CNS effects have been observed, including confusion, convulsions, myoclonia, hallucinations, and tremor.
Treatment. Treatment is symptomatic. ECG monitoring should be considered due to the possibility of QT interval prolongation. Antacids should be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis or CAPD, is not effective for removing levofloxacin from the body. There are no specific antidotes.
Side effects
The frequency of the adverse reactions listed below was determined using the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).
Within each group, adverse reactions are listed in order of decreasing severity.
Infections and infestations. Uncommon: fungal infections, including Candida species, microbial resistance.
Endocrine system disorders. Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Blood and lymphatic system disorders. Uncommon: leucopenia, eosinophilia. Rare: thrombocytopenia, neutropenia. Frequency not known: bone marrow function disorders, including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia.
Immune system disorders. Rare: angioneurotic oedema, hypersensitivity (see section "Special warnings and precautions for use"). Frequency not known: anaphylactic/anaphylactoid shock (see section "Special warnings and precautions for use").
Metabolism and nutrition disorders. Uncommon: anorexia. Rare: hypoglycaemia, mainly in patients with diabetes mellitus, hypoglycaemic coma (see section "Special warnings and precautions for use"). Frequency not known: hyperglycaemia (see section "Special warnings and precautions for use").
Psychiatric disorders*. Common: insomnia. Uncommon: anxiety, confusion, restlessness. Rare: psychotic reactions (including hallucinations, paranoia), depression, agitation, unusual dreams, nightmares, delirium, memory impairment. Frequency not known: psychotic reactions with self-destructive behaviour, including suicidal ideation or actions (see section "Special warnings and precautions for use"), mania.
Nervous system disorders*. Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia (subjective taste disturbance). Rare: convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), paraesthesia. Frequency not known: peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (movement coordination disorder), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hypertension, myoclonus.
Eye disorders*. Rare: visual disturbances such as blurred vision (see section "Special warnings and precautions for use"). Frequency not known: temporary vision loss (see section "Special warnings and precautions for use"), uveitis.
Ear and labyrinth disorders*. Uncommon: vertigo. Rare: tinnitus. Frequency not known: hearing loss, hearing impairment.
Cardiac disorders**. Rare: tachycardia, palpitations. Frequency not known: 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 ECG (see sections "Special warnings and precautions for use. QT interval prolongation" and "Overdose").
Vascular disorders**. Rare: arterial hypotension.
Respiratory system disorders. Uncommon: dyspnoea. Frequency not known: bronchospasm, allergic pneumonitis.
Gastrointestinal disorders. Common: diarrhoea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, flatulence/bloating, constipation. Frequency not known: haemorrhagic diarrhoea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis.
Hepatobiliary disorders. Common: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT). Uncommon: increased blood bilirubin levels. Frequency not known: jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use"), hepatitis.
Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special warnings and precautions for use"), persistent drug eruptions. Frequency not known: toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.
Musculoskeletal and connective tissue disorders*. Uncommon: arthralgia, myalgia. Rare: tendon disorders (see sections "Contraindications", "Special warnings and precautions for use"), including 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"). Frequency not known: rhabdomyolysis, tendon rupture (e.g., Achilles tendon) (see section "Special warnings and precautions for use"), ligament rupture, muscle rupture, arthritis.
Renal and urinary disorders. Uncommon: increased serum creatinine levels. Rare: acute renal failure (e.g., due to interstitial nephritis).
General disorders*. Uncommon: asthenia. Rare: increased body temperature (pyrexia). Frequency not known: pain (including back, chest and limb pain).
a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.
b Skin and mucous membrane reactions may sometimes occur even after 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 reactions have been reported, sometimes affecting multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration impairment, hearing, vision, taste and smell disturbances), sometimes occurring independently of risk factors (see section "Special warnings and precautions for use").
** In patients taking fluoroquinolones, cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported (see section "Special warnings and precautions for use").
Among other adverse effects associated with fluoroquinolone use, porphyria attacks have been observed in patients with a history of porphyria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions.
Shelf life. 3 years.
Storage conditions.
No special storage conditions required. Keep out of the reach and sight of children.
Packaging.
5 tablets in a blister; 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Actavis LTD.
Manufacturer's address and place of business.
BLB015, VLB 016 Bulbel Industrial Building, Zetun ZTN 3000, Malta.