Levofloxacin-teva

APPROVED by Order of the Ministry of Health of Ukraine

1. 03.2022 No. 536

Registration Certificate No. UA/11952/01/01; No. UA/11952/01/02 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 on 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 J01MA12.

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 complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship

The extent of antibacterial activity of levofloxacin depends on the ratio of peak serum concentration (Cmax) or area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance development

Resistance to levofloxacin develops gradually through mutations in the target site of type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability barriers (characteristic of 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, which 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 established MIC breakpoints for levofloxacin (version 2.0, 2012-01-01)

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 patterns raise uncertainty 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-susceptible, 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 exhibit 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; peak plasma concentrations (C_max) are 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. Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle content), 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. Following 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. The pharmacokinetics of levofloxacin are affected by renal impairment. With reduced renal function, renal elimination and creatinine clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Pharmacokinetics in renal impairment

after single oral 500 mg dose

Older patients. There are no significant differences in the pharmacokinetics of levofloxacin in younger and older 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;
• exacerbation of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• complicated skin and soft tissue infections;
• uncomplicated cystitis.

When treating the above-mentioned infections, the medicinal product should be used only when other antibacterial agents, typically prescribed 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 infusion.

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 damage associated with fluoroquinolone use.

Children and adolescents.

Pregnancy and lactation.

Interaction with other medicinal products and other types of interactions.

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 simultaneously with levofloxacin tablets. Concomitant administration of fluoroquinolones with multivitamin preparations containing zinc leads to 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 didanosine formulations containing aluminium or magnesium buffering agents) should not be administered within 2 hours before or after taking levofloxacin tablets (see section "Dosage and administration").

Calcium salts have minimal effect on the absorption of orally administered levofloxacin.

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 taking levofloxacin tablets.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs)

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when 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 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% with probenecid. This is explained by the fact that both drugs can block tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that statistically significant kinetic differences will have clinical relevance. Levofloxacin should be administered with caution concomitantly 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 administered 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 administered 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 concomitant vitamin K antagonists.

Medicinal products that prolong the QT interval

Levofloxacin, like 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 precautions. 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 a CYP1A2 inhibitor.

Other types of interactions

Corticosteroids

The risk of tendinitis and tendon rupture is increased in patients receiving concomitant corticosteroid therapy and levofloxacin. Therefore, concomitant use 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 regardless of food intake.

Special precautions for use.

Avoid using levofloxacin in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

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 known or suspected to be caused by MRSA, except in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and when use of 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 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, animal experimental 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 one or more body systems (musculoskeletal, nervous system, psychiatric, sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin 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, and 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 first symptoms of tendinitis (e.g., pain, swelling, inflammation) occur, levofloxacin treatment must be discontinued and alternative therapy considered. The affected limb(s) should receive appropriate treatment (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear.

Dosage adjustment is required for 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 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. Clostridium difficile-associated disease may range from mild to life-threatening; the most severe form is pseudomembranous colitis (see section "Adverse Reactions"). It is important to consider this diagnosis in patients who develop severe diarrhea during or after levofloxacin therapy. If Clostridium difficile-associated disease is suspected or confirmed, the medicinal product should be discontinued immediately and appropriate treatment initiated promptly. 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 (see section "Contraindications"). As with other quinolones, the medicinal product Levofloxacin-Teva should be used with extreme caution in patients predisposed to seizures and when used concomitantly with 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 susceptible to hemolytic reactions during treatment with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients, with monitoring for possible hemolysis.

Patients with renal impairment

Since levofloxacin is primarily excreted via the kidneys, dosage 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), including cases after the first dose (see section "Adverse Reactions"). Patients should discontinue treatment immediately and seek medical advice or emergency medical help.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions such as toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with levofloxacin use (see section "Adverse Reactions"). Patients should be informed of the signs and symptoms of these severe skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Reinitiation 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 levofloxacin treatment.

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 reported. Blood glucose levels should be monitored in diabetic patients. If blood glucose changes occur, levofloxacin treatment should be discontinued immediately and alternative non-fluoroquinolone antibiotic therapy considered.

Prevention of photosensitization

Although photosensitization is very rare with levofloxacin, patients are advised to avoid intense sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after its discontinuation.

Patients receiving vitamin K antagonists

Due to possible increases in coagulation test parameters (INR/aPTT) and/or bleeding in patients taking levofloxacin concomitantly with a vitamin K antagonist (e.g., warfarin), coagulation parameters should be monitored when these medicinal products are used together (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 long QT 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 imbalances (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 and sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. To prevent 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 fatal hepatic failure have been reported with levofloxacin use, 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, 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 post-marketing experience in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If visual disturbances or other effects on the eyes occur, an ophthalmologist should be consulted immediately (see sections "Ability to affect reaction speed when driving or operating machinery" and "Adverse Reactions").

Superinfection

With 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 regurgitation of 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 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 existing 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 in the emergency department if sudden abdominal, chest, or back pain occurs.

Patients should be advised to seek immediate medical help if acute dyspnea, new palpitations, or development of abdominal or lower limb edema occurs.

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 results in bacteriological testing of patients with tuberculosis.

Blood disorders

During treatment with levofloxacin, bone marrow suppression may occur, 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 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 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, 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 affect reaction speed 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 car or operating machinery).

Dosage and administration

Levofloxacin-Teva tablets are taken 1 or 2 times daily. The dosage depends on the type, severity of infection, and sensitivity of the likely pathogen.

Levofloxacin-Teva in this pharmaceutical form (film-coated tablets) may be used to complete the treatment course in patients who have shown improvement during initial therapy with levofloxacin infusion solution, using equivalent dosages, considering the bioequivalence of the parenteral and oral forms of the medicinal product.

Levofloxacin-Teva tablets should be swallowed whole, without chewing, with sufficient fluid. For convenience in dosing, the tablet may be divided along the score line. Tablets may be taken independently 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 types of interactions").

Table 3

Recommended dosage for adult patients with normal renal function
(creatinine clearance >50 mL/min)

Special populations

Table 4

Dosing for patients with impaired renal function (creatinine clearance ≤ 50 ml/min)

1 Additional doses are not required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Patients with hepatic impairment. Dose adjustment is not required, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Elderly patients. If renal function is not impaired, dose adjustment is not necessary (see section "Special precautions": 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 seizures); possible QT interval prolongation; and gastrointestinal reactions such as nausea and mucosal erosions.

During 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 potential for QT interval prolongation. Antacids may be used to protect the 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 according to 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 secretion of antidiuretic hormone (SIADH).

Blood and lymphatic system disorders. Uncommon: leucopenia, eosinophilia. Rare: thrombocytopenia, neutropenia. Frequency not known: bone marrow dysfunction, including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders. Rare: angioedema, 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-harming 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: seizures (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 (disturbance in coordination of movement), 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 loss of vision (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 damage, 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 of particular importance 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: pyrexia (elevated body temperature). 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 (lasting for months or years), disabling and potentially irreversible serious adverse reactions have been reported, sometimes affecting multiple body 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 disturbances, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration impairment, hearing, vision, taste and smell disturbances), in some cases regardless of the presence of risk factors (see section "Special warnings and precautions for use").

** In patients receiving 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 existing porphyria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested 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 category. Prescription only.

Manufacturer. Actavis LTD.

Manufacturer's address and place of business.

BLB015, VLB 016 Bulabel Industrial Building, Zetun ZTN 3000, Malta.