Levofloxacin, 5 mg/ml 100 ml

Pharmacotherapeutic group

Antimicrobial agent – fluoroquinolone

ATX code

J01MA

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.

Levofloxacin blocks DNA-giase and topoisomerase IV disrupts superspiralization and cross-linking of DNA breaks inhibits DNA synthesis and causes deep morphological changes in cytoplasm of cell wall and microbial cell membranes.

Levofloxacin is active against most strains of microorganisms in both in-vitro and in-vivo conditions.

Invitro

Sensitive microorganisms (MPC<2 mg/L; zone of inhibition >17 mm)

– Aerobic Gram-positive microorganisms: BacillusanthracisCorynebacteriumdiphtheriaeCorynebacteriumjeikeiumEnterococcusfaecalisEnterococcusspp. ListeriamonocytogenesStaphylococcuscoagulase-negativemethi-S/I[coagulazonegative methicillin-sensitive/ moderately sensitive] Staphylococcusaureusmethi-S(methicillin-sensitive) Staphylococcusepidermidismethi-S(methicillin-sensitive) Staphylococcusspp. CNS(coagulazonegative) Staphylococcus group C and GStreptococcusagalactiaeStreptococcuspneumoniaepeniI/S/R(penicillin-moderately sensitive/sensitive/resistant). StreptococcuspyogenesViridansstreptococcipeni-S/R(penicillin-sensitive/resistant).

– Aerobic Gram-negative microorganisms: AcinetobacterbaumanniiAcinetobacterspp. ActinobacillusactinomycetemcomitansCitrobacterfreundiiEikenellacorrodensEnterobacteraerogenesEnterobacteragglomeransEnterobactercloacaeEnterobacterspp. EscherichiacoliGardnerellavaginalisHaemophilusducreyiHaemophilusinfluenzaeampi- S/R(ampicillin-sensitive/resistant) HaemophilusparainfluenzaeHelicobacterpyloriKlebsiellaoxytocaKlebsiellapneumoniaeKlebsiellaspp. Moraxellacatarrhalisβ+/β- (producing and non-producing beta-lactamases) MorganellamorganiiNeisseriagonorrhoeaenonPPNG/PPNG (non-producing and producing penicillinases) NeisseriameningitidisPasteurellacanisPasteurelladagmatisPasteurellamultocidaPasteurellaspp. ProteusmirabilisProteusvulgarisProvidenciarettgeriProvidenciastuartiiProvidenciaspp. Pseudomonasaeruginosa (hospital infections caused by Pseudomonasaeruginosa may require combined treatment) Pseudomonasspp. Salmonellaspp. SerratiamarcescensSerratiaspp.

– Anaerobic microorganisms: BacteroidesfragilisBifidobacteriumspp. ClostridiumperfringensFusobacteriumspp. PeptostreptococcusPropionibacteriumspp. Veillonellaspp.

– Other microorganisms: Bartonellaspp. ChlamydiapneumoniaeChlamydiapsittaciChlamydiatrachomatisLegionellapneumophilaLegionellaspp. Mycobacteriumspp. MycobacteriumlepraeMycobacteriumtuberculosisMycoplasmahominisMycoplasmapneumoniaeRicketsiaspp. Ureaplasmaurealyticum.

Moderately sensitive microorganisms (MPC=4 mg/L; zone of inhibition – 16-14 mm):

– Aerobic Gram-positive microorganisms: Corynebacteriumurealyticum CorynebacteriumxerosisEnterococcusfaeciumStaphylococcusepidermidismethi-R(methicillin-resistant)Staphylococcoccushaemolyticusmethi-R(methicillin-resistant).

– Aerobic Gram-negative microorganisms: Campylobacterjejuni/coli.

– Anaerobic microorganisms: Prevotella spp. Porphyromonas spp.

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

– Aerobic Gram-positive microorganisms: Staphylococcusaureusmethi-R(methicillin-resistant) Staphylococcuscoagulase-negativemethi-R(coagulazonegative methicillin-resistant).

– Aerobic Gram-negative microorganisms: Alcaligenesxylosoxidans.

– Anaerobic microorganisms: Bacteroidesthetaiotaomicron.

– 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 (mechanism typical for Pseudomonasaeruginosa) and mechanism of efflux (active excretion of 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 following microorganisms)

– Aerobic Gram-positive microorganisms: EnterococcusfaecalisStaphylococcusaureus StreptococcuspneumoniaeStreptococcuspyogenes.

– Aerobic Gram-negative microorganisms: CitrobacterfreundiiEnterobactercloacaeEscherichiacoliHaemophilusinfluenzaeHaemophilusparainfluenzaeKlebsiellapneumoniaeMoraxella (Branhamella) catarrhalisMorganellamorganiiProteusmirabilisPseudomonasaeruginosaSerratiamarcescens.

– Other microorganisms: Chlamydiapneumoniae; LegionellapneumophilaMycoplasmapneumoniae.

Pharmacokinetics:

Absorption

After an intravenous 60-minute infusion of levofloxacin at a dose of 500 mg in healthy volunteers, the maximum plasma concentration (Cmaõ) averaged 62 µg/mL.

The pharmacokinetics of levofloxacin are linear in the dose range from 50 mg to 1000 mg. The equilibrium state of plasma concentration of levofloxacin when administered 500 mg of levofloxacin 1 or 2 times a day is reached within 48 hours.

Pa day 10 of intravenous administration of levofloxacin once daily, the plasma concentration of levofloxacin was 64±08 mcg/mL and the minimum plasma concentration of levofloxacin (concentration before administration of another dose) (Cmin) was 06±02 mcg/mL.

On day 10 of intravenous administration of the drug twice daily, the Cmax of levofloxacin was 79±11 mcg/ml and the Cmin was 23±05 mcg/ml.

Distribution.

The binding to serum proteins is 30-40%. Distribution volume of levofloxacin averaged 100 L after single and multiple intravenous administration of 500 mg which indicates good penetration of levofloxacin into human organs and tissues.

The penetration into the mucous membrane of the bronchial mucosa fluid epithelial lining alveolar macrophages

Levofloxacin penetrates well into bronchial mucosa and epithelial lining fluid of alveolar macrophages with penetration rates into bronchial mucosa and epithelial lining fluid compared to plasma concentrations of 11-18 and 08-3, respectively.

Penetration into pulmonary tissue

Levofloxacin penetrates well into pulmonary tissue with penetration coefficients of 2-5 compared to plasma concentrations.

Penetration in alveolar fluid

Levofloxacin penetrates well into alveolar fluid with a penetration coefficient of 1 compared to plasma concentrations. When levofloxacin was administered at 500 mg once or twice daily for 3 days, maximum concentrations of levofloxacin in alveolar fluid were achieved 2-4 hours after administration and were 40 and 67 mcg/ml, respectively.

Bone penetration

Levofloxacin penetrates well into cortical and cancellous bone tissue in both the proximal and distal femur with a penetration rate (bone tissue/blood plasma) of 01-3.

Cerebrospinal fluid penetration

Levofloxacin poorly penetrates cerebrospinal fluid.

Infiltration into prostate tissue

Levofloxacin penetrates well into prostate tissue (the average prostate/plasma concentration ratio was 184).

Concentrations in urine

Levofloxacin concentrations are high in the urine several times higher than plasma concentrations of levofloxacin.

Metabolism

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

Levofloxacin is relatively slowly excreted from the blood plasma after intravenous administration (elimination half-life [T1/2] is 6-8 hours). Excretion is mainly through the kidneys (more than 85% of the administered dose). Total clearance of levofloxacin after a single dose of 500 mg was 175±292 ml/min.

There are no significant differences in pharmacokinetics of levofloxacin with intravenous versus oral administration, confirming that the oral and intravenous routes of administration are interchangeable.

Pharmacokinetics in selected patient groups

The pharmacokinetics of levofloxacin do not differ in men and women.

Pharmacokinetics in elderly patients does not differ from that in younger patients except for differences in pharmacokinetics associated with differences in creatinine clearance (CK).

In renal failure the pharmacokinetics of levofloxacin changes. As renal function deteriorates, renal excretion and renal clearance (CLR) decreases and T1/2 increases.

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin in adults:

– community-acquired pneumonia;

– complicated urinary tract infections (including pyelonephritis);

– chronic bacterial prostatitis;

– infections of the skin and soft tissues;

– for complex treatment of drug-resistant forms of tuberculosis;

– prevention and treatment of anthrax through airborne droplets;

– acute sinusitis (as an alternative to other antimicrobial drugs);

– exacerbation of chronic bronchitis (as an alternative to other antimicrobial drugs);

– uncomplicated urinary tract infections (if there are these indications as an alternative to other antimicrobial drugs).

When using Levofloxacin, official national recommendations on the proper use of antibacterial drugs should be taken into account, as well as the sensitivity of pathogenic microorganisms in a particular country (see section “Special instructions”).

Pharmacological effect

Pharmacotherapeutic group

Antimicrobial agent – fluoroquinolone

ATX code

J01MA

Pharmacodynamics:

Levofloxacin is a synthetic broad-spectrum antibacterial drug from the group of fluoroquinolones containing levofloxacin, a left-handed isomer of ofloxacin, as an active substance.

Levofloxacin blocks DNA gyrase and topoisomerase IV; disrupts supercoiling and cross-linking of DNA breaks; inhibits DNA synthesis; causes profound morphological changes in the cytoplasm, cell wall and membranes of microbial cells.

Levofloxacin is active against most strains of microorganisms both in vitro and in vivo.

Invitro

Sensitive microorganisms (MIC17 mm)

– Aerobic gram-positive microorganisms: BacillusanthracisCorynebacteriumdiphtheriaeCorynebacteriumjeikeiumEnterococcusfaecalisEnterococcusspp. Listeria monocytogenes Staphylococcus coagulase-negativemethi-S/I [coagulase-negative methicillin-sensitive/-moderately sensitive] Staphylococcus aureusmethi-S (methicillin-sensitive) Staphylococcus epidermidismethi-S (methicillin-sensitive) Staphylococcus spp. CNS(coagulase-negative) Streptococcigroup C and GStreptococcusagalactiaeStreptococcuspneumoniaepeniI/S/R(penicillin-moderately sensitive/-sensitive/-resistant). StreptococcuspyogenesViridansstreptococcipeni-S/R(penicillin-sensitive/-resistant).

– Aerobic gram-negative microorganisms: Acinetobacter baumanniiAcinetobacter spp. Actinobacillus actinomycetemcomitansCitrobacterfreundiiEikenellacorrodensEnterobacteraerogenesEnterobacteragglomeransEnterobactercloacaeEnterobacterspp. EscherichiacoliGardnerellavaginalisHaemophilusducreyiHaemophilusinfluenzaeampi- S/R(ampicillin-sensitive/-resistant) HaemophilusparainfluenzaeHelicobacterpyloriKlebsiellaoxytocaKlebsiellapneumoniaeKlebsiellaspp. Moraxellacatarrhalisβ+/β- (producing and non-producing beta-lactamases) MorganellamorganiiNeisseriagonorrhoeaenonPPNG/PPNG (non-producing and producing nenicillinase) Neisseriameningitidis Pasteurellacanis Pasteurelladagmatis Pasteurellamultocida Pasteurellaspp. ProteusmirabilisProteusvulgarisProvidenciarettgeriProvidenciastuartiiProvidenciaspp. Pseudomonasaeruginosa (hospital infections caused by Pseudomonasaeruginosa may require combination treatment) Pseudomonaspp. Salmonellasp. SerratiamarcescensSerratiaspp.

– Anaerobic microorganisms: BacteroidesfragilisBifidobacteriumspp. Clostridium perfringens Fusobacterium spp. Peptostreptococcus Propionibacterium spp. Veillonellasp.

– Other microorganisms: Bartonella spp. ChlamydiapneumoniaeChlamydiapsittaciChlamydiatrachomatisLegionellapneumophilaLegionellaspp. Mycobacterium spp. MycobacteriumlepraeMycobacteriumtuberculosisMycoplasmahominisMycoplasmapneumoniaeRicketsiaspp. Ureaplasmaurealyticum.

Moderately sensitive microorganisms (MIC=4 mg/l; inhibition zone – 16-14 mm):

– Aerobic gram-positive microorganisms: Corynebacteriumurealyticum CorynebacteriumxerosisEnterococcusfaeciumStaphylococcusepidermidismethi-R(methicillin-resistant)Staphylococcushaemolyticusmethi-R(methicillin-resistant).

– Aerobic gram-negative microorganisms: Campylobacterjejuni/coli.

– Anaerobic microorganisms: Prevotella spp. Porphyromonas spp.

Microorganisms resistant to levofloxation (MIC >8 mg/l; inhibition zone <13 mm)

– Aerobic gram-positive microorganisms: Staphylococcus aureusmethi-R (methicillin-resistant) Staphylococcus coagulase-negativemethi-R (coagulase-negative methicillin-resistant).

– Aerobic gram-negative microorganisms: Alcaligenesxylosoxidans.

– Anaerobic microorganisms: Bacteroidesthetaiotaomicron.

– Other microorganisms: Mycobacterium avium.

Resistance

Resistance to levofloxacin develops as a result of a step-by-step process of mutations in the genes encoding both type II topoisomerases: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as the mechanism of influence on the penetration barriers of the microbial cell (a mechanism characteristic of Pseudomonasaeruginosa) and the mechanism of efflux (active removal of the antimicrobial agent from the microbial cell) may also reduce the sensitivity of microorganisms to levofloxacin.

Due to the peculiarities of the mechanism of action of levofloxacin, cross-resistance between levofloxacin and other antimicrobial agents is not usually observed.

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: CitrobacterfreundiiEnterobactercloacaeEscherichiacoliHaemophilusinfluenzaeHaemophilusparainfluenzaeKlebsiellapneumoniaeMoraxella (Branhamella) catarrhalisMorganellamorganiiProteusmirabilisPseudomonasaeruginosaSerratiamarcescens.

– Other microorganisms: Chlamydiapneumoniae; LegionellapneumophilaMycoplasmapneu­moniae.

Pharmacokinetics:

Absorption

After a 60-minute intravenous infusion of levofloxacin at a dose of 500 mg to healthy volunteers, the maximum plasma concentration (Cmax) averaged 62 μg/ml.

The pharmacokinetics of levofloxacin is linear in the dose range from 50 mg to 1000 mg. The equilibrium state of levofloxacin concentration in blood plasma with the administration of 500 mg of levofloxacin 1 or 2 times a day is achieved within 48 hours.

On the 10th day of intravenous administration of the drug once a day, the Cmax of levofloxacin was 64±08 mcg/ml and the minimum concentration of levofloxacin (concentration before the next dose) in the blood plasma (Cmin) was 06±02 mcg/ml.

On the 10th day of intravenous administration of the drug 2 times a day, Cmax of levofloxacin was 79±11 µg/ml and Cmin was 23±05 µg/ml.

Distribution.

The binding to serum proteins is 30-40%. The volume of distribution of levofloxacin averages 100 liters after single and multiple intravenous administration of 500 mg, which indicates good penetration of levofloxacin into organs and tissues of the human body.

Penetration into the bronchial mucosa fluid of the epithelial lining alveolar macrophages

Levofloxacin penetrates well into the bronchial mucosa, epithelial lining fluid, alveolar macrophages, with penetration coefficients into the bronchial mucosa and epithelial lining fluid, compared with concentrations in blood plasma of 11-18 and 08-3, respectively.

Penetration into lung tissue

Levofloxacin penetrates well into lung tissue with penetration coefficients of 2-5 compared to the concentration in blood plasma.

Penetration into alveolar fluid

Levofloxacin penetrates well into the alveolar fluid with a penetration coefficient of 1 compared to plasma concentrations. When levofloxacin was administered at a dose of 500 mg 1 or 2 times a day for 3 days, the maximum concentrations of levofloxacin in the alveolar fluid were reached 2-4 hours after administration and were 40 and 67 μg/ml, respectively.

Penetration into bone tissue

Levofloxacin penetrates well into cortical and cancellous bone tissue in both the proximal and distal parts of the femur with a penetration coefficient (bone tissue/blood plasma) of 01-3.

Penetration into the cerebrospinal fluid

Levofloxacin penetrates poorly into the cerebrospinal fluid.

Penetration into prostate tissue

Levofloxacin penetrates well into prostate tissue (the average prostate/blood plasma concentration ratio was 184).

Concentrations in urine

High concentrations of levofloxacin are created in the urine. several times higher than the concentrations of levofloxacin in the blood plasma.

Metabolism

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

Removal

After intravenous administration, levofloxacin is relatively slowly eliminated from the blood plasma (half-life [T1/2] – 6-8 hours). Excretion is predominantly through the kidneys (more than 85% of the dose taken). The total clearance of levofloxacin after a single dose of 500 mg was 175±292 ml/min.

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

Pharmacokinetics in selected patient groups

The pharmacokinetics of levofloxacin does not differ between men and women.

Pharmacokinetics in elderly patients does not differ from those in young patients, with the exception of differences in pharmacokinetics associated with differences in creatinine clearance (CC).

In renal failure, the pharmacokinetics of levofloxacin changes. As renal function deteriorates, renal excretion and renal clearance (CLR) decrease and T1/2 increases.

Special instructions

Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination treatment.

Risk of developing resistance

The prevalence of acquired resistance in cultured strains of microorganisms may vary by geographic region and over time. In this regard, information on drug resistance in a specific country is required. For the treatment of severe infections or when treatment is ineffective, a microbiological diagnosis must be established with the isolation of the pathogen and determination of its sensitivity to levofloxacin.

Methicillin-resistant Staphylococcus aureus

There is a high probability that methicillin-resistant Staphylococcus 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 Staphylococcus aureus if laboratory tests have not confirmed the sensitivity of this microorganism to levofloxacin.

Loss of ability to work (disability) and potential irreversible serious adverse reactions caused by the use of fluoroquinolones

The use of fluoroquinolones, including levofloxacin, has been associated with disability and the development of irreversible serious adverse reactions from various body systems that can develop simultaneously in the same patient. Adverse reactions caused by fluoroquinolones include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, as well as side effects from the nervous system (hallucinations, anxiety, depression, insomnia, headaches and confusion). These reactions may develop from several hours to several weeks after the start of levofloxacin therapy. The development of these adverse reactions was observed in patients of any age or without the presence of previous risk factors. If the first signs or symptoms of any serious adverse reactions occur, levofloxacin should be discontinued immediately. The use of fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced any of these serious adverse reactions.

Duration of infusion

You should strictly adhere to the recommended duration of drug administration, which should be at least 60 minutes (for 100 ml of infusion solution) or 30 minutes (for 50 ml of solution). Experience with the use of levofloxacin shows that during infusion, increased heart rate and a transient decrease in blood pressure may be observed. In rare cases, vascular collapse may develop. If a significant decrease in blood pressure is observed during the infusion, the drug administration is stopped immediately.

Patients predisposed to developing seizures

Like other quinolones, levofloxacin should be used with great caution in patients with a predisposition to seizures. Such patients include patients with previous lesions of the central nervous system such as stroke, severe traumatic brain injury; patients simultaneously taking drugs that lower the threshold of convulsive activity of the brain such as fenbufen and other similar non-steroidal anti-inflammatory drugs or other drugs that lower the threshold of convulsive activity such as theophylline (see section “Interaction with other drugs”). If seizures develop, treatment with levofloxacin should be discontinued.

Pseudomembranous colitis

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

Tendinitis and tendon rupture

When using quinolones, including levofloxacin, tendinitis is rare and can sometimes lead to tendon rupture, including the Achilles tendon, and can be bilateral. This side effect may occur within 48 hours of starting treatment or several months after completion of fluoroquinolone therapy. Elderly patients are more prone to developing tendinitis; 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 developing tendonitis, so it is recommended to be careful when prescribing fluoroquinolones to this category of patients. In patients with impaired nocturnal function, the daily dose should be adjusted based on creatinine clearance.

Patients should be advised to remain calm at the first sign of tendinitis or tendon rupture and to contact their healthcare provider. If tendonitis or tendon rupture is suspected, treatment with Levofloxacin should be stopped immediately and appropriate treatment of the affected tendon should be initiated, for example by providing adequate immobilization (see sections “Contraindications” and “Side Effects”)

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (angioedema, anaphylactic shock) (see section “Side effects”). If they develop, you should immediately stop administering the drug and immediately consult a doctor.

Severe bullous reactions

When taking levofloxacin, cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been observed (see section “Side effects”). In case of development of any reactions from the skin or mucous membranes, the patient should immediately inform the doctor who must decide on further use of the drug in the patient.

Disorders of the liver and biliary tract

Cases of hepatic necrosis, including the development of liver failure with a fatal outcome, have been reported with the use of levofloxacin, mainly in patients with severe underlying diseases such as sepsis (see section “Side effects”). Patients should be warned about the need to stop treatment and urgently consult a doctor if signs and symptoms of liver damage appear, such as anorexia, jaundice, dark urine, itching and abdominal pain.

Patients with impaired renal function

Since levofloxacin is excreted mainly through the kidneys in patients with impaired renal function, mandatory monitoring of renal function is required, as well as correction of the dosage regimen (see section “Dosage and Administration”). When treating elderly patients, it should be taken into account that patients in this group often have impaired renal function (see section “Method of administration and dosage”).

Preventing the development of photosensitivity reactions

Although photosensitivity during the use of levofloxacin develops very rarely, to prevent its development, patients are not recommended during treatment and for 48 hours after the end of treatment with levofloxacin to be unnecessarily exposed to strong solar or artificial ultraviolet irradiation (for example, visiting a solarium).

Superinfection

As with the use of other antibiotics, the use of levofloxacin, especially over a long period of time, can lead to increased proliferation of microorganisms that are insensitive to it (bacteria and fungi), which can cause changes in the microflora that is normally present in humans. As a result, superinfection may develop. Therefore, during treatment, it is imperative to re-evaluate the patient’s condition and, in the event of superinfection developing during treatment, appropriate measures should be taken.

QT prolongation

Very rare cases of QT prolongation have been reported in patients receiving fluoroquinolone therapy including levofloxacin.

When using fluoroquinolones, including levofloxacin, caution should be exercised in patients with known risk factors for prolongation of the QT interval: in elderly patients; in patients with uncorrected electrolyte disturbances (with hypokalemia and hypomagnesemia); with congenital long QT syndrome; with heart diseases (heart failure, myocardial infarction, bradycardia); with simultaneous use of drugs capable of prolonging the QT interval such as class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, neuroleptics.

Elderly and female patients may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution (see sections “With caution”, “Dosage and administration”, “Side effects”, “Overdose” and “Interaction with other drugs”).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency are predisposed to developing hemolytic reactions when treated with quinolones, which should be taken into account when treating with levofloxacin.

Hypo- and hyperglycemia (dysglycemia)

Potential risks of hypoglycemia, including the development of hypoglycemic coma, which is more common in older people and patients with diabetes mellitus who take oral hypoglycemic drugs or insulin. It is necessary to warn patients about the symptoms of hypoglycemia (confusion, dizziness, ravenous appetite, headache, nervousness, palpitations or increased pulse pallor of the skin, perspiration, trembling, weakness) and carefully monitor the concentration of glucose in the blood plasma in these patients (see section “Side Effects”)

Peripheral neuponamia

Cases of sensory and sensorimotor peripheral neuropathy, the onset of which may be rapid, have been reported in patients receiving fluoroquinolone therapy, including levofloxacin. If the patient develops symptoms of neuropathy, levofloxacin should be discontinued. This minimizes the possible risk of developing irreversible changes.

Patients should be informed to report any symptoms of neuropathy to their healthcare provider. Fluoroquinolones should not be prescribed to patients with a history of peripheral neuropathy.

Exacerbation of pseudoparalytic myasthenia gravis (myasthenia gravis)

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may increase muscle weakness in patients with myasthenia gravis. In the post-registration period, adverse reactions were observed, including pulmonary failure requiring mechanical ventilation and death, which were associated with the use of fluoroquinolones in patients with pseudoparalytic myasthenia gravis. The use of levofloxacin in a patient with an established diagnosis of pseudoparalytic myasthenia gravis is not recommended (see section “Side effects”).

Prevention and treatment of anthrax through airborne transmission

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

Psychotic reactions

Psychotic reactions including suicidal thoughts/attempts have been reported in patients using fluoroquinolones. including levofloxacin. The development of mental reactions is possible after a single dose. Treatment with fluoroquinolones should be stopped immediately if the patient reports any side effects from the central nervous system, including mental disturbances or decreased glucose concentrations. It is recommended to prescribe appropriate therapy; about switching in these cases to therapy with another antibiotic other than fluoroquinolones, if possible (see section “With caution”).

Visual impairment

If any visual impairment develops, immediate consultation with an ophthalmologist is necessary (see section “Side effects”).

Effect on laboratory tests

In patients receiving levofloxacin therapy, the determination of opiates in urine may lead to false-positive results which should be confirmed by more specific methods.

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

Precautions when handling the drug

To prevent bacterial contamination, the infusion solution should be used immediately (within 3 hours) after piercing the rubber stopper of the bottle. Protection of the solution from light during infusion is not required.

Impact on the ability to drive vehicles. Wed and fur.:

Side effects of Levofloxacin such as dizziness or vertigo, drowsiness and visual disturbances (see section “Side effects”) may reduce psychomotor reactions and the ability to concentrate. This may pose a certain risk in situations where these abilities are of particular importance (for example, when driving a car when servicing machines and mechanisms when performing work in an unstable position).

Active ingredient

Levofloxacin

Composition

Active ingredient: levofloxacin hemihydrate in terms of levofloxacin – 5 mg

Excipients: sodium chloride – 9 mg, hydrochloric acid solution 2 M – up to pH 4.3 – 5.3, water for injection – up to 1 ml

theoretical osmolarity 348 mOsm/l.

Pregnancy

Contraindicated during pregnancy and breastfeeding.

Contraindications

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

– childhood and adolescence up to 18 years of age (due to the incompleteness of skeletal growth, since the risk of damage to cartilaginous growth points cannot be completely eliminated);

– epilepsy;

– tendon damage with a history of fluoroquinolone use;

– pseudoparalytic myasthenia gravis (myasthenia gravis) (see sections “Side effects”, “Special instructions”).

– pregnancy (the risk of damage to the cartilaginous growth points of the fetus cannot be completely excluded);

– the period of breastfeeding (the risk of damage to the cartilaginous growth points of bones in a child cannot be completely eliminated).

With caution:

– In patients predisposed to the development of seizures [in patients with previous lesions of the central nervous system (CNS) in patients simultaneously taking drugs that lower the threshold of convulsive activity of the brain such as fenbufen theophylline] (see section “Interaction with other drugs”).

– In patients with latent or manifest deficiency of glucose-6-phosphate dehydrogenase (increased risk of hemolytic reactions when treated with quinolones).

– In patients with impaired renal function (mandatory monitoring of renal function is required, as well as correction of the dosage regimen, see section “Method of administration and dosage”).

– In patients with known risk factors for prolongation of the QT interval: in elderly patients; in female patients in patients with uncorrected electrolyte disturbances (with hypokalemia and hypomagnesemia); with congenital long QT interval syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); with simultaneous use of drugs capable of prolonging the QT interval (antiarrhythmic drugs of class IA and III, tricyclic antidepressants, macrolides, antipsychotics) (see sections “Overdose”, “Interaction with other drugs”, “Special instructions”)

– In patients with diabetes mellitus receiving treatment with oral hypoglycemic drugs (for example, glibenclamide) or insulin drugs (the risk of developing hypoglycemia increases).

– In patients with severe adverse reactions to other fluoroquinolones such as severe neurological reactions (increased risk of developing similar adverse reactions when using levofloxacin).

– In patients with psychosis or in patients with a history of mental illness (see section “Special instructions”).

– In elderly patients, in patients after transplantation, as well as with concomitant use of glucocorticosteroids (increased risk of tendonitis and tendon rupture) (see section “Special instructions”).

Side Effects

The side effects listed below are presented in accordance with the following gradations of frequency of their occurrence: very often (≥1/10); often (≥1/100 <1/10); uncommon (≥1/1000 <1/100); rare (≥1/10000 <1/1000); very rare (< 1/10000) (including isolated reports); frequency is unknown (but it is not possible to determine the frequency of occurrence based on the available data).

Data obtained in clinical trials and post-marketing use of the drug

Heart disorders

Rarely: sinus tachycardia, palpitations.

Frequency unknown (post-marketing data): prolongation of the QT interval, ventricular arrhythmias, ventricular tachycardia, ventricular tachycardia of the “pirouette” type, which can lead to cardiac arrest (see sections “Overdose” “Special instructions”).

Blood and lymphatic system disorders

Uncommon: leukopenia (decreased number of leukocytes in peripheral blood) eosinophilia (increased number of eosinophils in peripheral blood).

Rarely: neutropenia (decreased number of neutrophils in peripheral blood) thrombocytopenia (decreased number of platelets in peripheral blood).

Frequency unknown (post-marketing data): pancytopenia (decrease in the number of all formed elements in the peripheral blood), agranulocytosis (absence or sharp decrease in the number of granulocytes in the peripheral blood), hemolytic anemia.

Nervous system disorders

Common: headache, dizziness.

Uncommon: drowsiness, tremor, dysgeusia (taste perversion).

Rarely: paresthesia, convulsions (see section “Special instructions”).

Frequency unknown (post-marketing data): peripheral sensory neuropathy peripheral sensorimotor neuropathy (see section “Special Instructions”) dyskinesia extrapyramidal disorders ageusia (loss of taste) parosmia (disorder of the sense of smell, especially the subjective sensation of an objectively absent smell) including loss of smell syncope increased intracranial pressure (benign intracranial hypertension pseudotumor cerebri).

Violations of the organ of vision

Rarely: visual disturbances such as blurred vision.

Frequency unknown (post-marketing data): uveitis is transient loss of vision.

Hearing and labyrinth disorders

Uncommon: vertigo (a feeling of deviation or spinning of one’s own body or surrounding objects).

Rarely: ringing in the ears.

Frequency unknown (post-marketing data): hearing loss, hearing loss.

Disorders of the respiratory system of the chest and mediastinum

Uncommon: shortness of breath.

Frequency unknown (post-marketing data): bronchospasm, allergic pneumonitis.

Gastrointestinal disorders

Common: diarrhea, vomiting, nausea.

Uncommon: abdominal pain, dyspepsia, flatulence, constipation.

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

Renal and urinary tract disorders

Uncommon: increased serum creatinine concentration.

Rarely: acute renal failure (for example due to the development of interstitial nephritis).

Skin and subcutaneous tissue disorders

Uncommon: rash, itching, urticaria, hyperhidrosis.

Frequency unknown (post-marketing data): toxic epidermal necrolysis Stevens-Johnson syndrome exudative erythema multiforme photosensitivity reaction (increased sensitivity to solar and ultraviolet radiation) (see section “Special Instructions”) leukocytoclastic vasculitis stomatitis.

Reactions from the skin and mucous membranes can sometimes develop even after the first dose of the drug is administered.

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, myalgia.

Rarely: tendon involvement including tendonitis (eg Achilles tendon) muscle weakness which may be especially dangerous in patients with myasthenia gravis (see section “Special Instructions”).

Not known (post-marketing data): rhabdomyolysis, tendon rupture (eg Achilles tendon). This side effect can be observed within 48 hours after the start of treatment and can be bilateral (see also section “Special instructions”) ligament rupture muscle rupture arthritis.

Metabolic and nutritional disorders

Uncommon: anorexia.

Rarely: severe hypoglycemia up to the development of hypoglycemic coma, especially in elderly patients, patients with diabetes mellitus taking oral hypoglycemic drugs or insulin: voracious appetite, nervousness, perspiration, trembling). Frequency unknown: hyperglycemia, hypoglycemic coma (see section “Special instructions”).

Infectious and parasitic diseases

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

Vascular disorders

Common: phlebitis.

Rarely: decreased blood pressure.

General and administration site disorders

Often: reaction at the injection site (pain, skin flushing).

Uncommon: asthenia.

Rarely: pyrexia (fever).

Frequency unknown: pain (including pain in the back, chest, limbs).

Immune system disorders

Rarely: angioedema.

Frequency unknown (post-marketing data): anaphylactic shock, anaphylactoid shock.

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

Disorders of the liver and biliary tract

Often: increased activity of liver enzymes in the blood (for example, alanine aminotransferase (ALT), aspartate aminotransferase (ACT), increased activity of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GT).

Uncommon: increased concentration of bilirubin in the blood.

Frequency unknown (post-marketing data): severe liver failure including cases of acute liver failure, sometimes with a legal outcome, especially in patients with a severe underlying disease (for example, in patients with sepsis) hepatitis jaundice.

Mental disorders

Common: insomnia.

Uncommon: restlessness anxiety confusion.

Rarely: attention disorders, disorientation, agitation, nervousness, memory impairment, de­lyria.

Frequency unknown (post-marketing data): mental disorders with behavioral disorders with self-harm including suicidal thoughts and suicide attempts.

Other possible undesirable effects relevant to all fluoroquinolones

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

If you experience side effects indicated in the instructions or they get worse, or you notice any other side effects not listed in the instructions, please inform your doctor.

Interaction

Interactions requiring caution

With theophylline, fenbufen or similar drugs from the group of non-steroidal anti-inflammatory drugs that reduce the threshold of convulsive readiness of the brain

No pharmacokinetic interaction of levofloxacin with theophylline was detected. However, with the simultaneous use of quinolones and theophylline, non-steroidal anti-inflammatory drugs and other drugs that reduce the threshold of convulsive readiness of the brain, a pronounced decrease in the threshold of convulsive readiness of the brain is possible.

The concentration of levofloxacin while taking fenbufen increases only by 13%.

With indirect anticoagulants (vitamin K antagonists)

In patients taking levofloxacin in combination with indirect anticoagulants (for example, warfarin), an increase in prothrombin time/international normalized ratio and/or the development of bleeding, including severe bleeding, was observed. Therefore, with the simultaneous use of indirect anticoagulants and levofloxacin, regular monitoring of blood coagulation parameters is necessary.

With probenecid and cimetidine

With the simultaneous use of drugs that interfere with renal tubular secretion such as probenecid and cimetidine and levofloxacin, caution should be exercised, especially in patients with renal failure. The elimination (renal clearance) of levofloxacin is slowed down by cimetidine by 24% and probenecid by 34%. This is unlikely to be of clinical significance if renal function is normal.

With cyclosporine

Levofloxacin increased the half-life of cyclosporine by 33%. Since this increase is clinically insignificant, no dose adjustment of cyclosporine is required when used concomitantly with levofloxacin.

With glucocorticosteroids

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 taking drugs that prolong the QT interval (for example, class IA antiarrhythmics and III tricyclic antidepressants, macrolides, neuroleptics).

Others

Clinical and pharmacological studies conducted to study the possible pharmacokinetic interactions of levofloxacin with calcium carbonate, digoxin, glibenclamide, ranitidine and warfarin showed that the pharmacokinetics of levofloxacin, when used simultaneously with these drugs, does not change to a sufficient extent for this to be of clinical significance.

If you are using the above or other medications (including over-the-counter medications), consult your doctor before using Levofloxacin.

Overdose

Overdose symptoms

Based on data obtained from toxicological studies in animals, the most important expected symptoms of acute drug overdose are symptoms from the central nervous system (impaired consciousness including confusion, dizziness and convulsions).

During post-marketing use of the drug in case of overdose, effects from the central nervous system were observed, including confusion, convulsions, hallucinations and tremor.

Nausea and erosion of the gastrointestinal mucosa may develop. In clinical and pharmacological studies conducted with doses of levofloxacin exceeding therapeutic doses, prolongation of the QT interval was shown.

Treatment of overdose

In case of overdose, careful monitoring of the patient is required, including ECG monitoring. Treatment is symptomatic. Levofloxacin is not excreted by dialysis (hemodialysis, peritoneal dialysis and continuous outpatient peritoneal dialysis). There is no specific antidote.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life

4 years.

Do not use after expiration date.

Manufacturer

Dalkhimfarm, Russia