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 infections and inflammatory diseases caused by microorganisms sensitive to levofloxacin in adults:

– community-acquired pneumonia;

– complicated urinary tract infections (including pyelonephritis);

– chronic bacterial prostatitis;

–

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

– prevention and treatment of anthrax in the airborne route of infection;

– acute sinusitis (as an alternative to other antimicrobials);

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

– uncomplicated urinary tract infections (if indicated as an alternative to other antimicrobials).

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

Active ingredient

Composition

Active ingredient: levofloxacin hemihydrate converted to levofloxacin – 5 mg

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

Theoretical osmolarity 348 mOsm/L.

How to take, the dosage

The dosing regimen and duration of treatment

The dosing regimen is determined by the nature and severity of the infection and the sensitivity of the suspected pathogen.

The duration of treatment varies depending on the course of the disease. As with other antibiotics, treatment with Levofloxacin is recommended to be continued for at least 48-78 hours after body temperature normalization or significant eradication of the pathogen.

The treatment must not be interrupted or stopped prematurely without a physician’s indication.

Depending on the patient’s condition after a few days of treatment it is possible to switch from intravenous infusion to taking the same dose of the drug in tablets (because the bioavailability of levofloxacin when taking the drug tablets is 99-100%) (see section on Pharmacokinetics).

If the drug is accidentally missed, the missed dose should be administered as soon as possible and Levofloxacin should be continued according to the recommended dosing regimen.

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

– Community-acquired pneumonia: 500 mg levofloxacin 1-2 times daily (respectively daily dose of 500-1000 mg levofloxacin) – 7-14 days.

– Complicated urinary tract infections: 500 mg of levofloxacin once daily (respectively, daily dose of 500 mg of levofloxacin) – 7-14 days.

– Pyelonephritis: 500 mg of levofloxacin once daily (respectively, daily dose of 500 mg of levofloxacin) – 7-10 days.

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

– Chronic bacterial prostatitis: 500 mg levofloxacin once daily (respectively, daily dose of 500 mg levofloxacin) – 28 days.

– Skin and soft tissue infections: 500 mg of levofloxacin once or twice daily (respectively, daily dose of 500-1000 mg of levofloxacin) – 7-14 days.

– Complex treatment of drug-resistant forms of tuberculosis: but 500 mg of levofloxacin 1-2 times a day (respectively, daily dose of 500-1000 mg of levofloxacin) – up to 3 months.

Prevention and treatment of anthrax in case of airborne route of infection: 500 mg of levofloxacin 1 time per day (respectively, daily dose of 500 mg of levofloxacin) – for up to 8 weeks.

Dosing regimen in patients with hepatic impairment

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

The dosing regimen in elderly patients does not require dosing adjustment unless the CK is lower than 50 ml/min or lower.

How to use

The infusion solution of Levofloxacin is administered once or twice daily. Levofloxacin infusion solution is administered SLOWLY by intravenous drip. Duration of infusion of 1 vial of the preparation solution of 500 mg (100 ml with 500 mg of levofloxacin) must be at least 60 min in case of half of the vial (50 ml with 250 mg of levofloxacin) infusion duration must be at least 30 min (see section “Special indications”).

The drug Levofloxacin is compatible with the following infusion solutions: 09 % sodium chloride solution 5 % dextrose solution 25 % Ringer’s solution with dextrose combined solutions for parenteral nutrition (amino acids carbohydrates electrolytes). Levofloxacin solution should not be mixed with heparin or solutions that have an alkaline reaction (e.g. sodium bicarbonate solution).

After removal of the vial from the cardboard package the infusion solution may be kept under room light for no more than 3 days!

If there is no improvement after treatment, or if symptoms worsen or new symptoms develop, consult a physician. Use the drug only according to the indications and routes of administration and in the dosages specified in the instructions.

Interaction

Cautious Interactions

With phenbufen theophylline or similar drugs from the group of non-steroidal anti-inflammatory drugs decreasing cerebral seizure threshold

Pharmacokinetic interaction of levofloxacin with theophylline has not been found. However, with concomitant use of quinolones and theophylline, nonsteroidal anti-inflammatory drugs and other drugs which decrease cerebral seizure threshold may significantly decrease cerebral seizure threshold.

The concentration of levofloxacin with concomitant administration of phenbufen increases only by 13%.

With indirect anticoagulants (vitamin K antagonists)

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

With probenecid and cimetidine

When concomitant use of drugs that impair renal tubular secretion such as probenecid and cimetidine and levofloxacin care should be taken especially in patients with renal insufficiency. Excretion (renal clearance) of levofloxacin is slowed by 24% by cimetidine and 34% by probenecid. This is unlikely to be clinically relevant in normal renal function.

With cyclosporine

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

With glucocorticosteroids

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

With drugs prolonging the QT interval

Levofloxacin as well as other fluoroquinolones should be used with caution in patients taking drugs prolonging the QT interval (e.g. antiarrhythmic drugs of class IA and III tricyclic antidepressants macrolides neuroleptics).

Others

. Clinical and pharmacological studies to explore possible pharmacokinetic interactions of levofloxacin with calcium carbonate digoxin glibenclamide ranitidine and warfarin have shown that the pharmacokinetics of levofloxacin with these drugs does not change sufficiently to be of clinical significance.

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

Special Instructions

Hospital infections caused by Pseudomonas aeruginosa may require combined treatment.

The risk of developing resistance

The prevalence of acquired resistance of bacterial strains being bred may vary by geographic region and over time. This requires information about resistance to the drug in a particular country. 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 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 unless laboratory testing has confirmed the sensitivity of this organism to levofloxacin.

Disability (disability) and potential irreversible serious adverse reactions due to fluoroquinolones

The use of fluoroquinolones including levofloxacin has 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 previous risk factors. If the first signs or symptoms of any serious adverse reactions occur, the use of levofloxacin should be stopped immediately. The use of fluoroquinolones, including levofloxacin, should be avoided in patients who have had any of these serious adverse reactions.

The duration of infusion

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

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 injuries such as stroke or severe traumatic brain injury; patients concomitantly taking drugs which lower the threshold of cerebral seizure activity such as phenbufen and other similar non-steroidal anti-inflammatory drugs or other drugs which lower the threshold of seizure activity such as theophylline (see section “Interaction with other medicinal products”). If seizures develop, treatment with levofloxacin should be discontinued.

Pseudomembranous colitis

Diarrhea during or after treatment with levofloxacin which is particularly severe and persistent and/or with blood may be a symptom of pseudomembranous colitis caused by Clostridiumdifficile. 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 and can sometimes lead to tendon rupture including Achilles tendon and can 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 the development of tendonitis; in patients taking fluoroquinolones the risk of tendon rupture may increase with the simultaneous 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 nocicular function the daily dose should be adjusted based on creatinine clearance.

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

Levofloxacin may cause serious potentially fatal hypersensitivity reactions (angioedema anaphylactic shock) (see section “Side effects”). In case of these reactions the drug administration should be stopped immediately and the patient should immediately consult the doctor.

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”). In case of any reactions of the skin or mucous membranes the patient should immediately inform the physician, who should make a decision on further use of the drug in the patient.

Hepatic and biliary tract disorders

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

Patients with impaired renal function

Because levofloxacin is mainly excreted through 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 taken into account that patients of this group often have impaired renal function (see section “Dosage and administration”).

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

As with other antibiotics levofloxacin administration especially over a long period of time can lead to increased proliferation of microorganisms (bacteria and fungi) which are not sensitive to it and this can cause changes in the microflora which is normally present in humans. As a result, superinfection can develop. Therefore it is mandatory to reassess the patient’s condition during treatment and take appropriate measures if superinfection develops during treatment.

Translongation of the QT interval

Very rare cases of prolongation of the QT interval have been reported in patients receiving therapy with fluoroquinolones including levofloxacin.

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

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

Patients with glucose-6-phosphate dehydrogenase deficiency

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

Hypo- and hyperglycemia (dysglycemia)

Potential risks of hypoglycemia up to hypoglycemic coma, which is more common in elderly and diabetic patients who take oral hypoglycemic agents or insulin. It is necessary to warn patients about the symptoms of hypoglycemia (confusion dizziness “wolf” appetite headache nervousness sensation of palpitations or rapid pulse pale skin perspiration shivering weakness) to monitor closely the plasma glucose concentration in these patients (see.

Peripheral neuropathy

In patients receiving therapy with fluoroquinolones including levofloxacin, cases of sensory and sensory-motor peripheral neuropathy have been reported which may have a rapid onset. If a 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 to inform their physician of the appearance of any symptoms of neuropathy. Fluoroquinolones should not be prescribed in patients with a history of peripheral neuropathy.

Pseudoparalytic myasthenia gravis

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 lethal outcome were observed associated with fluoroquinolones administration 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 the data on the sensitivity to it of Bacillus anthracis obtained in in vitro studies and in experimental studies performed 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 the consensus view on the treatment of anthrax.

Psychotic reactions

Psychotic reactions including suicidal thoughts/attempts have been reported in patients when using fluoroquinolones. including levofloxacin. The development of psychotic reactions is possible after a single dose. Fluoroquinolones should be discontinued immediately if a patient reports any central nervous system adverse effects, including mental disturbances or decreased glucose concentrations. Appropriate therapy is recommended; switching to therapy with an antibiotic other than fluoroquinolones in these cases is recommended if possible (see section “Caution”).

Visual disturbances

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

Impact on laboratory tests

In patients treated with levofloxacin, urinary opioid determination may lead to false-positive results which must be confirmed by more specific methods.

Levofloxacin can inhibit the growth of Mycobacterium tuberculosis and may lead to subsequent false-negative bacteriologic diagnosis of tuberculosis.

Precautionary measures for handling the drug

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

Such side effects of Levofloxacin as dizziness or vertigo drowsiness 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 a car when operating machinery or machines while working in an unsteady position).

Contraindications

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

– childhood and adolescence under 18 years (due to incomplete skeletal growth, since the risk of cartilage growth points damage cannot be completely excluded);

– epilepsy;

– tendon damage with a history of fluoroquinolone use;

– pseudoparalytic myasthenia gravis (see “Myasthenia gravis”). sections “Side Effects” and “Special Precautions”).

Pregnancy (we cannot completely rule out the risk of affecting cartilaginous growth points in the fetus);

Breastfeeding (we cannot completely rule out the risk of affecting cartilaginous growth points in the baby).

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

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

– In patients with impaired renal function (mandatory renal function monitoring is required as well as dosage regimen adjustment see section “Dosage and administration”).

– In patients with known risk factors for QT interval prolongation: In elderly patients; in female patients with unadjusted electrolyte abnormalities (with hypokalemia hypomagnesemia); with congenital QT interval prolongation syndrome; with heart disease (heart failure myocardial infarction bradycardia); with concomitant use of drugs that can prolong the QT interval (antiarrhythmic drugs of class IA and III tricyclic antidepressants macrolides neuroleptics) (see “Overdose

– In patients with diabetes mellitus receiving treatment with oral hypoglycemic agents (e.g., glibenclamide) or insulin agents (increased risk of hypoglycemia).

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

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

– In elderly patients, post-transplant patients and concomitant use of glucocorticosteroids (increased risk of tendonitis and tendon rupture) (see section “Special Precautions”).

Side effects

The side effects listed below are presented according to the following frequency gradations: very common (≥1/10); common (≥1/100 < 1/10); infrequent (≥1/1000 < 1/100); rare (≥1/10000 < 1/1000); very rare (< 1 /10000) (including individual reports); frequency unknown (but no data available to determine frequency of occurrence).

Data from clinical studies and post-marketing use of the drug

Cardiac disorders

Rarely: sinus tachycardia palpitations.

Prevalence unknown (postmarketing data): prolongation of the QT interval ventricular arrhythmia ventricular tachycardia ventricular pirouette tachycardia which may lead to cardiac arrest (see sections “Overdose” “Special Precautions”).

Disorders of the blood and lymphatic system

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

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

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

Nervous system disorders

Often: headache dizziness.

Infrequent: drowsiness tremor dysgeusia (perversion of taste).

Rarely: paresthesia seizures (see section “Special Indications”).

Frequency unknown (post-marketing data): peripheral sensory neuropathy peripheral sensory-motor neuropathy (see section “Special Indications. Specific Indications) dyskinesia extrapyramidal disorders aguesia (loss of taste sensation) parosmia (disorder of smell sensation especially subjective sense of smell objectively absent) including loss of smell fainting increased intracranial pressure (benign intracranial hypertension pseudotumor brain tumor).

Visual disturbances

Rarely: visual disturbances such as blurred vision.

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

Hearing and labyrinth disorders

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

Rarely: ringing in the ears.

Infrequent unknown (postmarketing data): hearing loss hearing loss.

Respiratory system disorders of the thorax and mediastinum

Infrequent: dyspnea.

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

Gastrointestinal disorders

Often: diarrhea vomiting nausea.

Infrequent: 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 Indications”) pancreatitis.

Renal and urinary tract disorders

Infrequent: increase of serum creatinine concentration.

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

Skin and subcutaneous tissue disorders

Infrequent: rash itching urticaria hyperhidrosis.

Prevalence unknown (postmarketing data): toxic epidermal necrolysis Stevens-Johnson syndrome exudative erythema multiforme photosensitization reactions (hypersensitivity to sun 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.

Musculoskeletal 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-marketing data): rhabdomyolysis tendon rupture (e.g. Achilles tendon). This side effect may occur within 48 h after treatment initiation and may be bilateral (see also “Special Indications”) ligament tear muscle tear arthritis.

Disorders of metabolism and nutrition

Infrequent: anorexia.

Rarely: severe hypoglycemia up to hypoglycemic coma development especially in elderly patients with diabetes taking oral hypoglycemic agents or insulin: “wolf” appetite nervousness sweating shiver). Frequency unknown: hyperglycemia hypoglycemic coma (see section “Special Precautions”).

Infectious and parasitic diseases

Infrequent: fungal infections development of resistance of pathogens.

Vascular disorders

Often: phlebitis.

Rarely: decreased blood pressure.

General disorders and disorders at the site of administration

Often: reaction at the site of administration (soreness hyperemia of the skin).

Infrequent: asthenia.

Rarely: pyrexia (increase in body temperature).

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

Immune system disorders

Rarely: angioedema.

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

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

Hepatic and biliary tract disorders

Often: increased activity of “hepatic” enzymes in the blood (e.g. alanine aminotransferase (ALT) aspartate aminotransferase (ACT) increased activity of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GT).

Infrequent: increase of bilirubin concentration in blood.

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

Mental disorders

Often: insomnia.

Infrequent: anxiety anxiety confusion.

Rarely: attention deficit disorientation agitation nervousness memory impairment delirium.

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

Other possible adverse effects related to all fluoroquinolones

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

If you have any of the side effects mentioned in the instructions or if they get worse, or if you notice any other side effects not mentioned in the instructions, tell your doctor.

Overdose

Symptoms of overdose

Based on data from animal toxicology studies, the most important expected symptoms of acute overdose of the drug are central nervous system symptoms (disturbances of consciousness including confusion, dizziness and seizures).

In post-marketing use of the drug in overdose, central nervous system effects have been observed, including confusion, seizures, hallucinations and tremors.

Nausea and gastrointestinal mucosal erosion may occur. In clinical and pharmacological studies performed with doses of levofloxacin in excess of therapeutic doses, prolongation of the QT interval has been shown.

Treatment of overdose

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

Pregnancy use

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