Levomac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMAC (LEVOMAC)

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin 250 mg or 500 mg;

Excipients: microcrystalline cellulose, pregelatinized starch, polysorbate 80, crospovidone, talc, colloidal anhydrous silicon dioxide, magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), propylene glycol, diethyl phthalate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets of brown-red color, smooth on both sides (250 mg);

capsule-shaped, biconvex, film-coated tablets of brown-red color, smooth on both sides (500 mg).

Pharmacotherapeutic group.

Antibacterials for systemic use. Fluoroquinolones.

ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones and is the S-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

As a fluoroquinolone-class antibacterial agent, levofloxacin acts on the DNA-DNA gyrase and topoisomerase IV complex.

Pharmacokinetic / pharmacodynamic relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic curve (AUC) to the minimal inhibitory (suppressive) concentration (MIC (MPC)).

Mechanism of resistance

Resistance to levofloxacin develops through a stepwise process of mutations in the target sites of both 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 is observed between levofloxacin and other fluoroquinolones. Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not expected.

Breakpoint values

The recommended breakpoint values of MIC for levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant) and intermediate from resistant organisms, are listed in the MIC testing table (mg/L) below.

EUCAST clinical MIC breakpoint values for levofloxacin (version 10.0, 2020-01-01):

Pathogen	Susceptible	Resistant
Enterobacterales	≤ 0.5 mg/l	> 1 mg/l
Pseudomonas spp.	≤ 0.001 mg/l	> 1 mg/l
Acinetobacter spp.	≤ 0.5 mg/l	> 1 mg/l
Staphylococcus aureus (Coagulase-negative staphylococci)	≤ 0.001 mg/l	> 1 mg/l
Enterococcus spp.1	≤ 4 mg/l	> 4 mg/l
Streptococcus pneumoniae	≤ 0.001 mg/l	> 2 mg/l
Streptococcus A, B, C and G	≤ 0.001 mg/l	> 2 mg/l
Haemophilus influenzae	≤ 0.06 mg/l	> 0.06 mg/l
Moraxella catarrhalis	≤ 0.125 mg/l	> 0.125 mg/l
Helicobacter pylori	≤ 1 mg/l	> 1 mg/l
Aerococcus sanguinicola and urinae	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
PK/PD (Non-species-related) breakpoints	≤ 0.5 mg/l	> 1 mg/l
1: only uncomplicated urinary tract infections 2: Conclusion on susceptibility can be based on susceptibility to ciprofloxacin

The prevalence of resistance may vary geographically and over time for individual species, and local information on microbial resistance should be sought, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence is such that the benefit of the drug is at least questionable for some types of infections.

Commonly susceptible organisms Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococcus 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. Organisms where acquired resistance may be a problem Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, 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.

*Methicillin-resistant S. aureus is highly likely to exhibit co-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.

Absolute bioavailability is 99–100%.

Food has minimal effect on the absorption of levofloxacin.

Steady-state concentrations are achieved within 48 hours with a dosing regimen 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 tissue distribution throughout the body.

Penetration into tissues and body fluids. Levofloxacin penetration has been demonstrated into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Metabolism. Levofloxacin undergoes minimal metabolism. The metabolites identified are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the administered dose and are excreted in urine. Levofloxacin 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 (t½) is 6–8 hours). It is primarily excreted by the kidneys (> 85% of the administered dose).

Mean total systemic clearance of levofloxacin after a single 500 mg dose was

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 over the range of 50 to 1000 mg.

Patients with renal impairment. The pharmacokinetics of levofloxacin are affected by the degree of renal function impairment. With declining renal function, renal excretion and clearance decrease, and elimination half-life increases, as shown in the table below.

Pharmacokinetics in renal impairment after a single oral dose of 500 mg:

Creatinine clearance (ml/min)	< 20	20–49	50–80
Renal clearance (ml/min)	13	26	57
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.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of single-dose toxicity, repeated-dose toxicity, carcinogenic potential, and reproductive and developmental toxicity.

Levofloxacin did not impair fertility or reproductive performance in rats, and its only effect on the fetus was delayed maturation due to maternal toxicity.

Levofloxacin did not induce gene mutations in bacterial or mammalian cells, but induced chromosomal aberrations in Chinese hamster lung cells in vitro. These effects can be explained by inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not reveal genotoxic potential.

Studies in mice showed that levofloxacin has phototoxic potential only at very high doses.

Levofloxacin showed no genotoxic potential in a photomutagenicity study, and it reduced tumor development in a photocarcinogenicity study. Like other fluoroquinolones, levofloxacin demonstrated effects on cartilage (blisters and cavities) in rats and dogs. These findings were more pronounced in younger animals.

Clinical characteristics.

Indications.

The drug is indicated in adults for the treatment of the following infections:

• Acute pyelonephritis and complicated urinary tract infections.
• Chronic bacterial prostatitis.
• Inhalational anthrax: post-exposure prophylaxis and treatment.

For the above-mentioned infections, the drug should be used only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of these infections.
• Acute bacterial sinusitis.
• Exacerbation of chronic bronchitis.
• Community-acquired pneumonia.
• Complicated skin and soft tissue infections.
• Uncomplicated cystitis.

The drug may also be used to complete a course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment.
Official recommendations on the appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to levofloxacin or other quinolones, to any component of the drug, epilepsy, history of tendon-related adverse reactions following prior use of fluoroquinolones, age under 18 years, pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on the drug

Iron salts, zinc salts, antacids containing magnesium and aluminium, didanosine. Levofloxacin absorption is significantly reduced when administered concomitantly with iron salts or antacids containing magnesium or aluminium, or with didanosine (only for formulations containing aluminium or magnesium buffering agents). Concurrent administration of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption. It is not recommended to take medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium or magnesium buffering agents), within 2 hours before or after administration of levofloxacin. Calcium salts had minimal effect on the oral absorption of 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 levofloxacin administration (see section "Dosage and administration").

Theophylline, fenbufen, or other similar non-steroidal anti-inflammatory drugs

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 and non-steroidal anti-inflammatory drugs or other agents that reduce seizure threshold. Levofloxacin concentrations in the presence of fenbufen were approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both drugs are capable of blocking tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences had clinical relevance. Caution should be exercised when administering levofloxacin concomitantly with medicinal products that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other

Calcium carbonate, digoxin, glyburide, and ranitidine do not have any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly.

Effect of the drug on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (PT/INR) and/or bleeding, which may be severe, have been reported. Therefore, in patients receiving concomitant vitamin K antagonists, coagulation parameters should be monitored (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, antipsychotics) (see section "Special precautions for use" ("QT interval prolongation")).

Other important information

In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (a probe substrate for CYP1A2), indicating that levofloxacin is not an inhibitor of CYP1A2.

Other forms of interaction

Food intake

No clinically significant interaction with food has been observed. Levofloxacin tablets can therefore be taken independently of meals.

Special precautions for use.

The use of levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse reactions").

Treatment of these patients with levofloxacin should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

Resistance risk

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus 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 (conventional antibacterial agents recommended for MRSA infections are generally considered inappropriate).

Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis, provided these infections have been appropriately diagnosed.

Resistance to fluoroquinolones in Escherichia coli (the most common cause of urinary tract infections) varies across countries. Local prevalence of fluoroquinolone resistance in Escherichia coli should be taken into account when prescribing fluoroquinolones.

Inhalational anthrax: human use is based on in vitro susceptibility data for Bacillus anthracis, animal experimental data, and limited human study data. Physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

Long-term, disabling and potentially irreversible serious adverse drug reactions

In patients receiving quinolones and fluoroquinolones, very rare cases of long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems—sometimes multiple organ systems (musculoskeletal, nervous, psychiatric, and sensory organs)—have been reported, regardless of age or existing risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult their physician.

Tendinitis and tendon rupture

Tendinitis, which may lead to tendon rupture including of the Achilles tendon, may occur during treatment with quinolones. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting levofloxacin or even several months after discontinuation. Patients most at risk include those aged 60 years or older, those receiving a daily dose of 1000 mg levofloxacin, and those receiving concomitant corticosteroid therapy. Dose adjustment is required for elderly patients based on creatinine clearance. Therefore, monitoring of elderly patients is necessary when prescribing levofloxacin. If tendinitis is suspected, levofloxacin therapy should be discontinued immediately and appropriate treatment initiated (e.g., immobilization of the affected tendon).

Myoclonus

Cases of myoclonus have been reported in patients treated with 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 onset of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, or bloody diarrhea occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening, with the most severe form being pseudomembranous colitis (see section "Adverse reactions"). This diagnosis should therefore be considered in patients who develop severe diarrhea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, levofloxacin should be discontinued immediately and appropriate therapy initiated promptly. In such cases, drugs that inhibit intestinal motility are contraindicated.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy.

As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures or 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 seizures occur, levofloxacin therapy should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions when treated with quinolone antibacterial agents. Therefore, if levofloxacin must be administered to such patients, potential hemolysis should be monitored.

Renal impairment

Levofloxacin is primarily excreted via the kidneys; therefore, dose adjustment is required in patients with renal impairment.

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (including angioedema, anaphylactic shock), even after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin adverse reactions

Severe skin adverse reactions (SCAR), 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 and may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed of the signs and symptoms of serious skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Levofloxacin therapy must not be restarted in patients who have experienced a serious reaction such as SJS, TEN, or DRESS during previous treatment.

Blood glucose alterations

As with all quinolones, disturbances in blood glucose levels, including hypoglycemia and hyperglycemia, occur more frequently in elderly patients, particularly in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section "Adverse reactions").

Prolonged treatment should be discontinued immediately if the patient reports disturbances in blood glucose, and alternative non-fluoroquinolone antibacterial therapy should be considered.

Prevention of photosensitivity reactions

Photosensitivity reactions have been reported during treatment with levofloxacin.

To prevent photosensitivity reactions, patients taking levofloxacin should avoid exposure to sunlight and UV radiation (UV lamps, tanning beds) due to possible photosensitization during and for 48 hours after discontinuation of levofloxacin.

Patients taking vitamin K antagonists

Coagulation parameters should be monitored in patients receiving concomitant levofloxacin and vitamin K antagonists (e.g., warfarin) due to the potential risk of increased coagulation parameters (prothrombin time/INR) and/or bleeding.

Psychotic reactions

Psychotic reactions have been observed in patients receiving quinolones, including levofloxacin. In rare cases, these have led to suicidal thoughts and self-harming behavior—sometimes even after a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with a history of psychotic disorders or psychiatric illness.

QT interval prolongation

Cases of QT interval prolongation have been reported with fluoroquinolone use. Caution should be exercised when administering fluoroquinolones, including levofloxacin, to patients with known risk factors for QT prolongation:

• congenital or acquired QT prolongation syndrome;
• concomitant use of medicinal products that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• electrolyte imbalance (including hypokalemia, hypomagnesemia);
• cardiac disease (heart failure, myocardial infarction, bradycardia).

Elderly patients and women are more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones.

Patients receiving levofloxacin should be advised to inform their physician before continuing treatment if they experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, to prevent development of potentially irreversible conditions (see section "Adverse reactions").

Hepatobiliary disorders

Cases of hepatic necrosis up to life-threatening liver 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 their physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Myasthenia gravis

Fluoroquinolones, including levofloxacin, inhibit neuromuscular transmission and may provoke 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 disorders

If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Adverse reactions" and "Ability to influence reaction rate when driving or operating machinery").

Superinfection

With the use of levofloxacin, particularly prolonged use, opportunistic infections and overgrowth of resistant microorganisms may occur. Appropriate measures should be taken if secondary infection develops.

Laboratory tests

False-positive urine opiate screening results may occur in patients receiving levofloxacin. Confirmation of positive opiate results using specific methods may be necessary.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis and may therefore result in false-negative bacteriological test results in patients with tuberculosis.

Aortic aneurysm and dissection, valvular regurgitation/insufficiency

Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with existing aneurysm and/or aortic dissection or heart valve disease, or in the presence of other risk factors or conditions predisposing to:

• both aortic aneurysm and dissection and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis), or additionally
• aortic aneurysm and dissection (e.g., vascular diseases such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or additionally
• valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and rupture may also be increased in patients receiving concomitant systemic corticosteroids.

Patients should be advised to seek immediate medical attention in case of sudden abdominal, chest, or back pain.

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

Acute pancreatitis

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued; if confirmed, levofloxacin therapy should not be resumed. Caution should be exercised in patients with a history of pancreatitis (see section "Adverse reactions").

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during treatment with levofloxacin (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.

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 with regard to reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of fluoroquinolone-induced damage to the weight-bearing joint cartilage of the growing organism, levofloxacin should not be administered during pregnancy.

Breastfeeding. Levofloxacin is contraindicated in women who are breastfeeding. Information on the excretion of levofloxacin into breast milk is insufficient, although other fluoroquinolones are known to be excreted into breast milk. Due to the lack of human studies and the potential for fluoroquinolone-induced damage to the weight-bearing joint cartilage of the growing organism, levofloxacin should not be administered to women who are breastfeeding.

Fertility. It is known that levofloxacin did not cause disorders of fertility or reproductive function 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 car or operating machinery).

Dosage and administration

The medication should be taken once or twice daily. The dosage depends on the type and severity of the infection. The duration of treatment depends on the course of the disease. Levomak tablets in this dosage 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 the same dosage regimen, taking into account the bioequivalence of the parenteral and oral forms of the drug.

Levomak tablets should be swallowed whole without chewing, with an adequate amount of liquid. If necessary, the tablet may be divided along the score line. The tablets may be taken with or without food. Levofloxacin tablets should be taken at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only didanosine formulations with buffering agents containing aluminum or magnesium), or sucralfate, as reduced absorption may occur (see section "Interaction with other medicinal products and other forms of interaction").

The following dosage recommendations apply to adults with normal renal function (creatinine clearance >50 mL/min):

Indications	Daily dose (depending on severity)	Duration of treatment (depending on severity)
Acute bacterial sinusitis	500 mg once daily	10–14 days
Acute bacterial exacerbations of chronic obstructive pulmonary disease, including bronchitis	500 mg once daily	7–10 days
Community-acquired pneumonia	500 mg 1–2 times daily	7–14 days
Acute pyelonephritis	500 mg once daily	7–10 days
Complicated urinary tract infections	500 mg once daily	7–14 days
Uncomplicated cystitis	250 mg once daily	3 days
Chronic bacterial prostatitis	500 mg once daily	28 days
Complicated skin and soft tissue infections	500 mg 1–2 times daily	7–14 days
Inhalational anthrax	500 mg once daily	8 weeks

Special populations

Renal impairment (creatinine clearance ≤ 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	subsequent: 125–250 mg/ 24 hours	subsequent: 250 mg/ 24 hours	subsequent: 250 mg/ 12 hours
19–10 mL/min	subsequent: 125–250 mg/ 48 hours	subsequent: 125–250 mg/ 24 hours	subsequent: 125–250 mg/ 12 hours
<10 mL/min (including hemodialysis and CAPD1)	subsequent: 125–250 mg/ 48 hours	subsequent: 125–250 mg/ 24 hours	subsequent: 125–250 mg/ 24 hours

1After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.

2Since the tablet is not scored, when prescribing the drug at doses less than 250 mg, levofloxacin formulations allowing such dosing should be used.

Dosing in patients with hepatic impairment. Dose adjustment is not required, as levofloxacin is minimally metabolized in the liver and primarily excreted by the kidneys.

Dosing in elderly patients. If renal function is normal, there is no need for dose adjustment.

Pediatric population.

The drug is contraindicated in children under 18 years of age.

Overdose.

Based on toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic, the most important signs expected after acute levofloxacin overdose include central nervous system symptoms such as confusion, dizziness, altered consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, central nervous system effects including confusion, seizures, myoclonus, hallucinations, and tremor have been observed. In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Antacids may be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions

The information below is based on data from clinical studies in more than 8,300 patients and extensive post-marketing experience with levofloxacin.

The frequency is defined according to the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency group, adverse reactions are listed in order of decreasing frequency.

System Organ Class	Common (≥1/100 to <1/10)	Uncommon (≥1/1000 to <1/100)	Rare (≥1/10000 to <1/1000)	Not known (cannot be estimated from available data)
Infections and infestations		Fungal infection, including infection caused by Candida species Resistance of pathogenic microorganisms
Blood and lymphatic system disorders		Leukopenia Eosinophilia	Thrombocytopenia Neutropenia	Bone marrow depression, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia
Immune system disorders			Angioedema Hypersensitivity	Anaphylactic shock Anaphylactoid reaction
Endocrine disorders			Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus Hypoglycemic coma	Hyperglycemia
Psychiatric disorders*	Insomnia	Anxiety Confusion Nervousness	Psychotic reactions (e.g., with hallucinations, paranoia) Depression Agitation Unusual dreams Nightmares Delirium	Psychotic reactions with self-destructive behavior, including suicidal ideation or actions, mania
Nervous system disorders*	Headache Dizziness	Somnolence Tremor Dysgeusia	Seizures Paraesthesia Memory impairment	Peripheral sensory neuropathy Peripheral sensorimotor neuropathy Parosmia, including anosmia Dyskinesia Extrapyramidal disorders Ageusia Syncope Benign intracranial hypertension Myoclonus
Eye disorders*			Visual disturbances, such as blurred vision	Transient loss of vision Uveitis
Ear and labyrinth disorders*		Vertigo	Tinnitus	Hearing loss Hearing impairment
Cardiac disorders**			Tachycardia Palpitations	Ventricular tachycardia, which may lead to cardiac arrest Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT interval prolongation) Prolonged QT interval on ECG
Vascular disorders**	Applies only to IV formulations: Phlebitis		Hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm Allergic pneumonia
Gastrointestinal disorders	Diarrhea Vomiting Nausea	Abdominal pain Dyspepsia Abdominal distension Constipation		Hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis Pancreatitis
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated blood bilirubin		Jaundice and severe liver injury, including cases of fatal acute liver failure, predominantly in patients with severe underlying diseases Hepatitis
Skin and subcutaneous tissue disorders		Rash Pruritus Urticaria Hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS), fixed drug eruption	Toxic epidermal necrolysis Stevens-Johnson syndrome Multiform erythema Photosensitivity reactions Leukocytoclastic vasculitis Stomatitis Skin hyperpigmentation
Musculoskeletal and connective tissue disorders*		Arthralgia Myalgia	Tendon disorders, including tendonitis (e.g., Achilles tendon) Muscle weakness, which may be significant in patients with myasthenia gravis	Rhabdomyolysis Tendon rupture (e.g., Achilles tendon) Ligament rupture Muscle rupture Arthritis
Renal and urinary disorders		Increased serum creatinine	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions	Applies only to IV formulations: Injection site reactions (pain, redness)	Asthenia	Pyrexia	Pain (including back, chest and limb pain)

aAnaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

bCutaneous and mucosal reactions may sometimes occur even after the first dose.

Other adverse reactions associated with the use of fluoroquinolones:

porphyria attacks in patients with porphyria.

* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple organ systems and sensory organs have been reported with quinolones and fluoroquinolones (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell); anxiety, suicidal thoughts, panic attacks, neuralgia, and difficulty concentrating have also been reported as potential components of prolonged and disabling adverse reactions associated with fluoroquinolones (see section "Special precautions").

** Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), as well as regurgitation / insufficiency of any heart valve have been reported in patients receiving fluoroquinolones (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

5 tablets in a blister, 1 or 2 blisters in a cardboard pack; 5 tablets in a blister; 4 interconnected blisters, 5 such blister units in a cardboard pack;

10 tablets in a blister; 10 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and site of operations.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.