Levofloxacin, 500 mg 5 pcs

Pharmacotherapeutic group: Antimicrobial agent – fluoroquinolone

ATX code: J01MA12

Pharmacological properties

Pharmacodynamics

Levofloxacin is a synthetic broad spectrum antibacterial drug from the group of fluoroquinolones, containing levofloxacin – the left-handed isomer ofloxacin as the active substance. It blocks DNA-enzyme (topoisomerase II) and topoisomerase IV, breaks superspiralization and cross-linking of DNA breaks, inhibits DNA synthesis, causes deep morphological changes in cytoplasm, cell wall and membranes of sensitive microorganisms.
Levofloxacin is active against most strains of microorganisms both in vitro and in vivo.

In vitro

Sensitive microorganisms (MPC ≤ 2 mg/L; zone of inhibition ≥ 17 mm)

– Aerobic Gram-positive microorganisms: Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp. Enterococcus faecalis, Listeria monocytogenes, Staphylococcus coagulase-negativemethi-S(I) [coagulase-negative methicillin-sensitive/ moderately sensitive, Staphylococcus aureus methi-S (methicillin-sensitive), Staphylococcus epidermidis methi-S (methicillin-sensitive), Staphylococcus spp. CNS (coagulazonegative), Streptococci u G, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumonia peni I/S/R (penicillin-moderately sensitive/sensitive/resistant), Viridans streptococci peni-S/R (penicillin-sensitive/resistant).

– Aerobic Gram-negative microorganisms: Acinetobacter baumanii, Acinetobacter spp., Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter spp, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenza ampi-S/R (ampicillin sensitive/resistant), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella spp, Moraxela catarrhalis β+/β- (producing and non-producing beta-lactamases), Morganella morganii, Neisseria gonorrhoeae non PPNG/PPNG (not producing and producing penicillinase), Neisseria meningitidis, Pasteurella canis, Pasteurella dagmatis, Pasteurella multocida Pasteurella spp, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii Providencia spp. Pseudomonas aeruginosa (hospital infections caused by Pseudomonas aeruginosa may require combined treatment), Pseudomonas spp., Salmonella spp., Serratia marcescens, Serratia spp.

– Anaerobic microorganisms: Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus, Propionibacterium spp., Veilonella spp.

– Other microorganisms: Bartonella spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp., Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma hominis, Mycoplasma pneumoniae, Rickettsia spp. , Ureaplasma urealyticum.

Moderately susceptible microorganisms (MPC = 4 mg/L; inhibition zone 16-14 mm)

– Aerobic Gram-positive microorganisms: Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R(methicillin-resistant), Staphylococcus haemolyticus methi-R (methicillin-resistant).

– Aerobic Gram-negative microorganisms: Campylobacter jejuni/coli.

– Anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Levofloxacin-resistant microorganisms (MPC > 8mg/L; zone of inhibition < 13 mm)

– Aerobic Gram-positive microorganisms: Staphylococcus aureus methi-R (methicillin-resistant), Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant).

– Aerobic Gram-negative microorganisms: Alcaligenes xylosoxidans.

– Anaerobic microorganisms: Bacteroides thetaiotaomicron.

– Other microorganisms: Mycobacterium avium.

Resistance

Resistance to levofloxacin develops as a result of a stepwise process of mutations in the genes encoding both type II topoisomerases: DNA-Gyrase and topoisomerase IV. Other mechanisms of resistance, such as the mechanism of influence on the penetration barriers of the microbial cell (a mechanism characteristic of Pseudomonas aeruginosa) and the mechanism of efflux (active elimination of the antimicrobial agent from the microbial cell), can also decrease the sensitivity of microorganisms to levofloxacin.

In view of the specific mechanism of action of levofloxacin there is usually no cross-resistance between levofloxacin and other antimicrobial agents.

Clinical efficacy (effectiveness in clinical studies in the treatment of infections caused by the microorganisms listed below):

– Aerobic Gram-positive microorganisms: Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes.

– Aerobic Gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzaemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

– Others: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Pharmacokinetics

Absorption

Levofloxacin is quickly and almost completely absorbed after oral administration; food has little effect on its absorption. Absolute bioavailability when administered orally is 99-100%. After a single use of 500 mg of levofloxacin maximum concentration in blood plasma (Cmax) is reached within 1-2 hours and is 5.2±1.2 µg/ml. Pharmacokinetics of levofloxacin is linear in the range from 50 to 1000 mg. The equilibrium state of plasma concentrations of levofloxacin when receiving 500 mg of levofloxacin 1 or 2 times a day is reached within 48 hours.

On day 10 of oral administration of 500 mg of levofloxacin once daily, the Cmax of levofloxacin was 5.7 ± 1.4 µg/ml, and the minimum plasma concentration of levofloxacin (concentration before the next dose) (Cmin) was 0.5 ± 0.2 µg/ml.

On day 10 of oral administration of 500 mg of levofloxacin twice daily, the Cmax was 7.8 ± 1.1 µg/ml and the Cmin was 3.0 ± 0.9 µg/ml.

Distribution

The binding to serum proteins is 30-40%. After single and repeated administration of 500 mg of levofloxacin the volume of distribution of levofloxacin averaged 100 l which indicates good penetration of levofloxacin into human organs and tissues.

Infiltration into the bronchial mucosa, epithelial lining fluid, alveolar macrophages

. After a single oral dose of 500 mg of levofloxacin, maximum concentrations of levofloxacin in bronchial mucosa and epithelial lining fluid were reached within 1 h or 4 h and were 8.3 µg/g and 10.8 µg/mL, respectively, with penetration rates in bronchial mucosa and epithelial lining fluid, compared to plasma concentrations of 1.1-1.8 and 0.8-3, respectively.

After 5 days of oral administration of 500 mg of levofloxacin, mean concentrations of levofloxacin 4 hours after the last drug administration in the epithelial lining fluid were 9.94 µg/mL and in alveolar macrophages were 97.9 µg/mL.

Pulmonary tissue penetration

The maximum pulmonary tissue concentrations after oral administration of 500 mg of levofloxacin were approximately 11.3 µg/g and were reached 4-6 h after drug administration with penetration ratios of 2-5, compared to plasma concentrations.

Perfusion in alveolar fluid

. After 3 days of administration of 500 mg of levofloxacin 1 or 2 times daily, maximum concentrations of levofloxacin in alveolar fluid were reached 2-4 hours after drug administration and were 4.0 and 6.7 µg/ml, respectively, with a penetration factor of 1, compared to plasma concentrations.

Bone penetration

Levofloxacin penetrates well into cortical and cancellous bone tissue in both the proximal and distal femur, with a penetration ratio (bone tissue/plasma) of 0.1-3. Maximum levofloxacin concentrations in the cancellous bone tissue of the proximal femur after oral administration of 500 mg of the drug were approximately 15.1 µg/g (2 hours after drug administration).

Cerebrospinal fluid penetration

Levofloxacin poorly penetrates into the cerebrospinal fluid.

Permeasurement in prostate tissue

After oral administration of 500 mg of levofloxacin once daily for 3 days, the average concentration of levofloxacin in prostate tissue was 8.7 µg/g and the average prostate/plasma concentration ratio was 1.84.

Urinary concentrations

The mean urinary concentrations 8-12 h after oral doses of 150, 300, and 600 mg of levofloxacin were 44 µg/mL, 91 µg/mL, and 162 µg/mL, respectively.

Metabolism

Levofloxacin is metabolized to a small extent (5% of the dose taken). Its metabolites are demethyllevofloxacin and levofloxacin N-oxide, which are excreted by the kidneys. Levofloxacin is stereochemically stable and does not undergo chiral transformations.

Levofloxacin is relatively slowly eliminated from the blood plasma after oral administration (elimination half-life (T1/2) is 6-8 hours). Excretion is mainly through the kidneys (more than 85% of the dose taken). Total clearance of levofloxacin after a single dose of 500 mg was 175 ± 29.2 ml/minute.

There are no significant differences in the pharmacokinetics of levofloxacin when administered intravenously and when administered orally, confirming that oral and intravenous administration are interchangeable.

Pharmacokinetics in selected patient groups

The pharmacokinetics of levofloxacin do not differ in men and women. Pharmacokinetics in elderly patients do not differ from those in younger patients, except for differences in pharmacokinetics associated with differences in creatinine clearance (CK).

In renal insufficiency, the pharmacokinetics of levofloxacin changes. As renal function decreases, renal excretion and renal clearance (CIR) decrease and T1/2 increases.

Pharmacokinetics in renal failure after a single oral dose of 500 mg of the drug.

Indications

Treatment of infections and inflammatory diseases caused by microorganisms sensitive to levofloxacin:

– Outpatient pneumonia;
– Hospital pneumonia (for 750 mg dosage);
– Complicated urinary tract infections and pyelonephritis;
– Chronic bacterial prostatitis;
– Skin and soft tissue infections;
– For complex treatment of drug-resistant forms of tuberculosis;
– Syphilis anthrax prevention and treatment in case of disseminated infection.

For treatment of the following infectious and inflammatory diseases levofloxacin can be used only as an alternative to other antimicrobial agents:

– acute sinusitis;
– exacerbation of chronic bronchitis;
– uncomplicated cystitis.

When using the drug Levofloxacin the official national guidelines for the appropriate use of antibacterial agents as well as the sensitivity of pathogenic microorganisms in a particular country should be taken into account (see section “Special directions”).

Active ingredient

Composition

Composition per tablet:

Active ingredient: levofloxacin hemihydrate which is equivalent to levofloxacin – 512.46 mg (500.00 mg).

Excipients: microcrystalline cellulose – 44.69 mg; crosspovidone – 7.85 mg; sodium stearyl fumarate – 1.41 mg; croscarmellose sodium – 6.15 mg; colloidal silica – 15.38 mg; maltodextrin – 24.60 mg; magnesium stearate – 2.46 mg.

The shell: OPADRY Orange 20A230018 – 15,000 mg [hydroxypropyl methylcellulose 2910/hypromellose 6 cP (E464) – 6,600 mg; titanium dioxide (E171) – 1,375 mg; talc, 3.150 mg; hyprolose (hydroxypropyl cellulose, clucel EF) (E463), 3.851 mg; sunset yellow dye (E 110), 0.024 mg].

How to take, the dosage

Tablets of Levofloxacin 250 mg, 500 mg or 750 mg are taken orally once or twice a day. The tablets should be swallowed without chewing and with plenty of fluid (0.5 to 1 cup).

The drug can be taken before meals or at any time between meals, since eating has no effect on absorption of the drug (see section “Pharmacokinetics”).

The drug should be taken at least 2 hours before or 2 hours after taking drugs containing magnesium and/or aluminum, iron, zinc or sucralfate (see section “Interaction with other medicinal products”).

Given that the bioavailability of levofloxacin when taken in tablets is 99-100%, if the patient is switched from intravenous infusion of levofloxacin to taking tablets the treatment should be continued in the same dose that was used for intravenous infusion (see section “Pharmacokinetics”).

If one or more doses of the medication are missed, the next dose should be taken as soon as possible and the medication should be continued according to the recommended dosing regimen.

Doses and duration of treatment

The dosing regimen is determined by the type and severity of the infection and also by the sensitivity of the suspected pathogen. The duration of treatment varies depending on the course of the disease.

The recommended dosing regimen and duration of treatment in patients with normal renal function (CK > 50 ml/min)

– Community-acquired pneumonia: 2 tablets 250 mg or 1 tablet 500 mg 1-2 times daily (respectively 500-1000 mg of levofloxacin) -7-14 days. Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-moderately sensitive/sensitive/resistant), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae – 1 tablet 750 mg once daily – 5 days.

– Hospital pneumonia: 1 tablet 750 mg once daily – 7-14 days.

– Complicated urinary tract infections: 2 tablets 250 mg once daily or 1 tablet 500 mg once daily (500 mg levofloxacin respectively) – 7-14 days.

In treatment of complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and acute pyelonephritis caused by Escherichia coli, including cases with concomitant bacteremia – 1 tablet 750 mg once daily for 5 days.

– Pyelonephritis: 2 tablets 250 mg once daily or 1 tablet 500 mg once daily (500 mg of levofloxacin, respectively) – 7-10 days.

– Chronic bacterial prostatitis: 2 tablets 250 mg or 1 tablet 500 mg once daily (500 mg levofloxacin, respectively) – 28 days.

– Skin and soft tissue infections: 2 tablets 250 mg or 1 tablet 500 mg 1-2 times per day (500-1000 mg of levofloxacin, respectively) – 7-14 days. In complicated infections of the skin and soft tissues: 1 tablet of 750 mg 1 time per day – 10-14 days.

– Complex treatment of drug-resistant forms of tuberculosis: 1 tablet of 500 mg 1-2 times per day (respectively 500-1000 mg of levofloxacin) – up to 3 months.

– Prevention and treatment of anthrax in case of airborne route of infection: 2 tablets 250 mg or 1 tablet 500 mg (500 mg of levofloxacin, respectively) 1 time daily for up to 8 weeks.

– Acute sinusitis: 2 tablets 250 mg or 1 tablet 500 mg once daily

(500 mg levofloxacin, respectively) for 10-14 days; 1 tablet 750 mg once daily for 5 days.

– Acute exacerbation of chronic bronchitis: 2 tablets 250 mg or 1 tablet 500 mg once daily (500 mg of levofloxacin, respectively) – 7-10 days.

– Uncomplicated cystitis: 1 tablet 250 mg once daily (respectively, 250 mg levofloxacin) – 3 days.

Dosing regimen in patients with impaired renal function (CK ≤50 ml/min).

Dosing regimen in patients with hepatic impairment

There is no need for dosing regimen correction in patients with hepatic impairment because levofloxacin is only slightly metabolized in the liver.

The dosing regimen in elderly patients

The dosing regimen does not need to be adjusted in elderly patients unless the CK falls to 50 ml/min or lower.

Interaction

Cautious interactions

With drugs containing magnesium, aluminum, iron and zinc, didanosine

Drugs containing bivalent or trivalent cations, such as zinc and iron salts (drugs to treat anemia), magnesium -and/or aluminum-containing drugs (such as antacids), didanosine (only dosage forms containing aluminum or magnesium as a buffer) are recommended to be taken at least 2 hours before or 2 hours after taking Levofloxacin.

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

With sucralfate

The effect of levofloxacin is significantly impaired with concomitant use of sucralfate (gastric mucosal protection agent). Patients receiving levofloxacin and sucralfate are recommended to take sucralfate 2 hours after taking levofloxacin.

With theophylline, phenbufen or similar drugs from the group of non-steroidal anti-inflammatory drugs that reduce the threshold of cerebral seizure activity.

Pharmacokinetic interaction of levofloxacin with theophylline has not been revealed. However, with concomitant administration of quinolones and theophylline, nonsteroidal anti-inflammatory drugs and other drugs that reduce cerebral seizure threshold, a pronounced decrease in cerebral seizure threshold is possible. Concentration of levofloxacin is increased by only 13% when concomitant administration of fenbufen.

With indirect coagulants

In patients treated with levofloxacin in combination with indirect anticoagulants (e.g., warfarin) an increase in prothrombin time/normalized international ratio and/or development of bleeding has been observed, including severe bleeding. Therefore, when concomitant use of indirect anticoagulants and levofloxacin, regular monitoring of blood clotting parameters is necessary.

With probenicid and cimetidine

When concomitant use of drugs that interfere with renal tubular secretion of levofloxacin, such as probenicid and cimetidine, caution should be exercised especially in patients with renal insufficiency. The excretion (renal clearance) of levofloxacin is slowed by 24% by cimetidine and 34% by probenecidine It is unlikely that this may be of clinical significance in normal renal function.

With cyclosporine

Levofloxacin increases the half-life of cyclosporine by 33%. Since this increase is clinically insignificant, there is no need to adjust the dose of cyclosporine when using it concomitantly with levofloxacin.

With glucocorticosteroids

The concomitant use of glucocorticosteroids increases the risk of tendon rupture.

With drugs that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs that prolong the QT interval (e.g., Class IA and III antiarrhythmic agents, tricyclic antidepressants, macrolides, neuroleptics).

Other

. The results of the clinical and pharmacological studies to investigate possible pharmacokinetic interactions of levofloxacin with digoxin, glibenclamide, ranitidine, warfarin showed that pharmacokinetics of levofloxacin with these drugs does not change sufficiently to be of clinical significance.

Special Instructions

Hospital infections caused by Pseudomjnas aeruginosa may require combination therapy.

The risk of developing resistance

The prevalence of acquired resistance of absorbed microbial strains may vary by geographic region and over time. Therefore, information on resistance to the drug in a particular country is required. For therapy of severe infections or in case of ineffective treatment it is necessary to establish microbiological diagnosis with pathogen isolation and determination of its sensitivity to levofloxacin.

Methicillin-resistant streptococcus aureus

There is a high probability that methicillin-resistant streptococcus aureus will be resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of established or suspected infections caused by methicillin-resistant streptococcus aureus if laboratory tests have not confirmed the sensitivity of this microorganism to levofloxacin.

Disability (disability) and potential irreversible serious adverse reactions due to fluoroquinolones
Fluoroquinolones, including levofloxacin, have been associated with disability and irreversible serious adverse reactions in various body systems that can occur simultaneously in the same patient.

Fluoroquinolones-induced adverse reactions include tendonitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and nervous system side effects (hallucinations, anxiety, depression, insomnia, headaches, and confusion). These reactions may occur within a few hours to a few weeks after the start of therapy with levofloxacin. The development of these adverse reactions has been noted in patients of any age or without prior risk factors.

The first signs or symptoms of any serious adverse reactions should be immediately discontinued with levofloxacin. The use of fluoroquinolones, including levofloxacin, should be avoided in patients who have had any of these serious adverse reactions.

Patients susceptible to seizures

Like other quinolones, levofloxacin should be used with great caution in patients with a predisposition to seizures. These patients include those with previous central nervous system lesions, such as stroke, severe craniocerebral trauma; patients concomitantly receiving drugs that lower the cerebral seizure threshold, such as phenbufen and other similar non-steroidal anti-inflammatory drugs or other drugs that lower the seizure threshold such as theophylline (see
Treatment with levofloxacin should be discontinued if seizures develop.

Pseudomembranous colitis

Diarrhea during or after treatment with levofloxacin, especially severe, persistent and/or with blood may be a symptom of pseudomembranous colitis caused by Clostridium diffieile. If pseudomembranous colitis is suspected, treatment with levofloxacin should be stopped immediately and specific antibiotic therapy (oral vancomycin, teicoplanin or metronidazole) started immediately. Drugs that inhibit intestinal peristalsis are contraindicated.

Tendinitis and tendon rupture

Tendinitis is rarely seen with quinolones, including levofloxacin, which can sometimes lead to tendon rupture, including of the Achilles tendon, and may be bilateral. This side effect may develop within 48 hours of starting treatment or several months after completion of fluoroquinolone therapy.

Elderly patients are more prone to develop tendonitis; in patients taking fluoroquinolones, the risk of tendon rupture may increase with concomitant use of glucocorticosteroids. In addition, patients after transplantation have an increased risk of tendinitis, so caution is recommended when prescribing fluoroquinolones for this category of patients. In patients with impaired renal function the daily dose should be adjusted on the basis of creatinine clearance.

Patients should be advised to remain at rest at the first signs of tendinitis or tendon rupture, and to consult their physician. If tendonitis or tendon rupture is suspected, treatment with the drug should be stopped immediately and appropriate treatment of the affected tendon should be initiated, such as adequate immobilization (see contraindications and side effects).

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (angioedema, anaphylactic shock), even when initial doses are used (see section “Side effects”). Patients should immediately stop taking the drug and consult a physician.

Serious bullous reactions

There have been cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis when taking levofloxacin (see section “Adverse effects”). If any skin or mucous membrane reactions develop, the patient should immediately consult a physician and do not continue treatment until he or she has been consulted.

Hepatic and biliary tract disorders

Cases of hepatic necrosis, including development of hepatic failure with fatal outcome, have been reported when using levofloxacin, mainly in patients with severe underlying diseases, such as sepsis (see section “Adverse effects”). Patients should be warned to discontinue treatment and seek urgent medical attention if signs and symptoms of liver damage, such as anorexia, jaundice, darkened urine, itching and abdominal pain appear.

Patients with renal impairment

Because levofloxacin is excreted mainly by the kidneys, in patients with impaired renal function it is necessary to monitor renal function and adjust the dosing regimen (see section “Dosage and administration”). When treating elderly patients it should be borne in mind that patients of this group often have impaired renal function.

Preventing photosensitization reactions

While photosensitization by levofloxacin is very rare, to prevent its development patients are not recommended during the treatment and within 48 hours after treatment with levofloxacin to be exposed to strong sunlight or artificial ultraviolet radiation without any special need (for example, to visit a solarium).

Superinfection

Like the use of other antibiotics, the use of levofloxacin, especially for a long time, may lead to increased reproduction of microorganisms (bacteria and fungi) that are not sensitive to it, which may cause changes in the microflora that are normally present in humans. As a result, superinfection may develop. Therefore, it is imperative that the patient is reassessed during treatment and if superinfection develops during treatment, appropriate measures should be taken.

Long QT interval

Very rare cases of long QT interval have been reported in patients treated with fluoroquinolones, including levofloxacin.

When using fluoroquinolones, including levofloxacin, caution should be exercised in patients with known risk factors for QT interval prolongation: In patients with uncorrected electrolyte abnormalities (with hypokalemia, hypomagnesemia); with congenital QT interval prolongation syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); with concomitant administration of drugs that can prolong the QT interval, such as class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, neuroleptics.

The elderly and female patients may be more sensitive to QT interval prolonging drugs. Therefore fluoroquinolones including levofloxacin should be used with caution in these patients (see sections Caution, Dosage and administration, Side effects, Overdose, Interaction with other medicinal products).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency have a predisposition to hemolytic reactions when treated with quinolones and this must be considered when treating with levofloxacin.

Hypo- and hyperglycemia (dysglycemia)

As with other quinolones, cases of hyperglycemia and hypoglycemia have been observed with levofloxacin. During therapy with levofloxacin dysglycemia occurred more frequently in elderly patients and patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) and insulin. When levofloxacin is used in these patients the risk of hypoglycemia increases, up to hypoglycemic coma.

Patients should be informed about the symptoms of hypoglycemia (confusion, dizziness, wolfish appetite, headache, nervousness, palpitations or increased pulse rate, pale skin, sweating, tremors, weakness) (see section “Side effects”). If the patient develops hypoglycemia, treatment with levofloxacin should be stopped immediately and an appropriate therapy should be started. In these cases it is recommended to switch to therapy with another antibiotic other than fluoroquinolones, if possible. During treatment with levofloxacin in elderly patients with diabetes mellitus, close monitoring of blood glucose concentration is recommended.

Peripheral neuropathy

In patients taking fluoroquinolones, including levofloxacin, cases of sensory and sensory-motor peripheral neuropathy have been reported, which may have a rapid onset. If the patient develops symptoms of neuropathy, the use of levofloxacin should be discontinued. This minimizes the possible risk of developing irreversible changes. Patients should be informed of the need to report any symptoms of neuropathy to their physician. Fluoroquinolones should not be prescribed in patients with a history of peripheral neuropathy.

Pseudoparalytic myasthenia gravis exacerbation

Fluoroquinolones, including levofloxacin, are characterized by blocking neuromuscular conduction activity and may exacerbate muscle weakness in patients with pseudoparalytic myasthenia gravis. In the post-registration period, adverse reactions, including pulmonary failure requiring artificial ventilation, and death have been observed that have been associated with fluoroquinolone use in patients with pseudoparalytic myasthenia gravis. The use of levofloxacin in a patient with a confirmed diagnosis of pseudoparalytic myasthenia gravis is not recommended (see section “Side effects”).

The use of levofloxacin in humans for this indication is based on data on the sensitivity of Bacillus anthracis in in vitro studies and in experimental studies conducted on animals, as well as on limited data on the use of levofloxacin in humans. Treating physicians should refer to national and/or international documents that reflect a consensus view on the treatment of anthrax.

Psychotic reactions

Psychotic reactions, including suicidal thoughts/attempts, have been reported in patients taking fluoroquinolones, including levoflocacin, sometimes after a single dose. In case of development of any side effects on the central nervous system, including mental disorders, treatment with levofloxacin should be stopped immediately and appropriate therapy should be prescribed. In these cases it is recommended to switch to therapy with another antibiotic other than fluoroquinolones, if possible. Caution should be exercised when prescribing the drug in patients with psychosis or patients with a history of mental illness.

In case of such reactions, treatment with levofloxacin should be discontinued and appropriate therapy prescribed. Caution should be exercised when prescribing the drug in patients with psychosis or patients with a history of mental illness.

VIight impairment

If any visual impairment develops, immediate consultation with an ophthalmologist is necessary (see section on side effects).

Impact on laboratory tests

In patients taking levofloxacin, urinary opioid determination may give false-positive results, which must be confirmed by more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and subsequently lead to false-negative bacteriological diagnosis of tuberculosis.

Impact on driving and operating ability

Such side effects of Levofloxacin as dizziness or vertigo, somnolence and visual disturbances (see section “Side effects”) may reduce psychomotor reactions and ability to concentrate. This may pose some risk in situations where these abilities are particularly important (e.g., driving, operating machinery, working in unsteady positions).

Contraindications

– Hypersensitivity to levofloxacin or other quinolones, as well as to any of the excipients of the drug;

– epilepsy;

– tendon lesions with a history of fluoroquinolones;

– pseudoparalytic myasthenia gravis (see

– childhood and adolescence

Side effects

The side effects listed below are presented according to the following frequency gradations: very frequently (≥ 1/10), frequently (≥ 1/100 to < 1/10), infrequently (≥ 1/1000 to < 1/100), rarely (≥ 1/10000 to < 1/1000), very rarely (< 1/10000), unspecified frequency (no data available to determine frequency of occurrence).

Cardiac disorders:

Rare: sinus tachycardia, palpitations, unspecified frequency – Frequency unknown (post-registration data): QT interval prolongation, ventricular arrhythmias, ventricular tachycardia, pirouette-type ventricular tachycardia, which can lead to cardiac arrest (see See sections “Overdose” and “Special Precautions”).

Disorders of the blood and lymphatic system:

Infrequent: leukopenia, eosinophilia.

Rarely: neutropenia, thrombocytopenia.

Prevalence unknown (post-registration data): pancytopenia, agranulocytosis, hemolytic anemia.

Nervous system disorders:

Often: headache, dizziness.

Infrequent: drowsiness, tremor, dysgeusia (perversion of taste).

Rarely – paresthesia, seizures (see section “Special Precautions”).

Prevalence is unknown (post-registration data): peripheral sensory neuropathy, peripheral sensory-motor neuropathy (see section “Special Precautions”).

Peripheral sensory neuropathy, dyskinesia, extrapyramidal disorders, agueusia (loss of sense of taste), parosmia (disorder of sense of smell, especially subjective sense of smell objectively absent) including loss of smell, syncope, increased intracranial pressure (benign intracranial hypertension, pseudotumor of the brain).

Visual disorders:

Rarely: blurring of the visible image.

Prevalence unknown (post-registration data): transient vision loss, uveitis.

Hearing and labyrinth disorders:

Infrequent: vertigo (feeling of deviation, spinning of own body or surrounding objects).

Rarely: ringing in the ears.

Frequency unknown (post-registration data): decreased hearing, hearing loss.
Respiratory system, thoracic and mediastinal disorders:

Infrequent: dyspnea.

Infrequent unknown (post-registration data): bronchospasm, allergic pneumonitis.

Gastrointestinal disorders:

Often: diarrhea, vomiting, nausea.

Infrequent: abdominal pain, dyspepsia, flatulence, constipation.

Prevalence unknown (post-registration data): hemorrhagic diarrhea, which in very rare cases may be a sign of enterocolitis, including pseudomembranous colitis (see section “Special indications”), pancreatitis.

Rare: Renal and urinary tract disorders:

Infrequent: increase of serum creatinine concentration;

Rarely: acute renal failure (e.g., due to development of interstitial nephritis).

Skin and subcutaneous tissue disorders

Infrequent: rash, itching, urticaria, hyperhidrosis.

Prevalence unknown (post-registration data): toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme exudative, photosensitization reactions (hypersensitivity to sunlight and ultraviolet radiation) (see section “Special Indications”), leukocytoclastic vasculitis, stomatitis.

Skin and mucous membrane reactions may sometimes develop even after the first dose of the drug.

Muscular and connective tissue disorders

Infrequent: arthralgia, myalgia.

Rarely: tendonitis, including tendonitis (e.g., Achilles tendon), muscle weakness, which can be especially dangerous in patients with pseudoparalytic myasthenia gravis (see section “Special Precautions”).

Prevalence unknown (post-registration data): rhabdomyolysis, tendon rupture (e.g., Achilles tendon. This side effect may occur within 48 h after the start of treatment and may be bilateral (see section “Special Precautions”)), ligament tears, muscle tears, arthritis.

Disorders of metabolism and nutrition

Infrequent: anorexia.

Rarely: hypoglycemia, especially in patients with diabetes mellitus (possible signs of hypoglycemia: “wolf” appetite, nervousness, sweating, trembling).

Prevalence unknown: hyperglycemia, severe hypoglycemia, up to development of

Hypoglycemic coma, especially in elderly patients, diabetic patients taking oral hypoglycemic agents or insulin (see section “Special Indications”).

Infectious and parasitic diseases

Infrequent: fungal infections, development of resistance of pathogenic microorganisms.

Vascular disorders

Rarely: decrease in blood pressure.

General disorders

Infrequent: asthenia.

Rarely: pyrexia (increased body temperature).

Prevalence unknown: pain (including pain in the back, chest and extremities).

Immune system disorders

Rarely: angioedema.

Frequency unknown (post-registration data): anaphylactic shock,

anaphylactoid shock.

Anaphylactic and anaphylactoid reactions may sometimes develop even after the first dose of the drug.

Liver and biliary tract disorders

Often: Increased activity of “hepatic” enzymes in the blood (e.g.,

alanine aminotransferase (ALAT), aspartate aminotransferase (AsAT)), increased activity of alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT).

Infrequent: increase of bilirubin concentration in blood.

Prevalence unknown (post-registration data): severe liver failure, including cases of acute liver failure, sometimes with fatal outcome, especially in patients with severe underlying disease (e.g., patients with sepsis) (see section “Special Indications”); hepatitis, jaundice.

Mental disorders

Often: insomnia.

Infrequent: anxiety, restlessness, confusion.

Rarely: psychiatric disorders (e.g., hallucinations, paranoia), depression, agitation (agitation), sleep disturbances, nightmares.

Frequency unknown (post-registration data): mental disorders with self-harm behavioral disorders, including suicidal ideation and suicide attempts, attention deficit disorder, disorientation, nervousness, memory impairment, delirium.

Other possible adverse effects relevant to all fluoroquinolones

Very rare: attacks of porphyria (a very rare metabolic disease) in patients with porphyria.

Overdose

Symptoms of overdose

Based on data obtained in toxicological studies of levofloxacin in animals, the most important expected symptoms of acute

Levofloxacin overdose are symptoms of the central nervous system (disorders of consciousness, including confusion, dizziness and seizures).

When levofloxacin is used in overdose, central nervous system effects have been observed, including confusion, seizures, hallucinations and tremors.

The development of nausea and gastrointestinal mucosal erosions may occur.

In clinical and pharmacological studies conducted with doses of levofloxacin greater than therapeutic, prolongation of the QT interval was observed.

Treatment of overdose

In case of overdose, close patient monitoring is required, including electrocardiogram monitoring. Treatment is symptomatic. In case of acute overdose gastric lavage and administration of antacids to protect the gastric mucosa are indicated. Levofloxacin is not excreted by dialysis (hemodialysis, peritoneal dialysis and continuous ambulatory peritoneal dialysis). There is no specific antidote.

Pregnancy use

Similarities