Levofloxacin

General characteristics. Structure:

Active ingredient: 250 mg or 500 mg of a levofloksatsin (in the form of a gemigidrat) in 1 tablet.

Excipients: lactoses monohydrate, cellulose microcrystallic, gipromelloza, кросповидон, magnesium stearate.

Cover: film covering (polyvinyl alcohol, titanium dioxide, macrogoal, talc, dye red charming, dye quinolinic yellow, indigo carmine.

Pharmacological properties:

Pharmacodynamics. Ftorkhinolon, antimicrobic microbicide of a broad spectrum of activity. Blocks DNK-girazu (topoisomerase II) and topoisomerase IV, breaks superspiralling and a stitching of ruptures of DNA, suppresses DNA synthesis, causes profound morphological changes in cytoplasm, a cell wall and membranes of bacteria. The main mechanism of development of resistance is connected with gyr-A gene mutation with possible development of cross resistance between levofloksatsiny and other ftorkhinolona. Cross resistance between levofloksatsiny and antibacterial drugs of other classes usually does not arise.

Activity of in vitro. Sensitive microorganisms (minimum overwhelming concentration <2 mg/l):

Aerobic gram-positive microorganisms: Bacillus anthracis, Corynebacterium diphtheria, Corynebacterium jeikeium. Enterococcus spp. (including Enterococcus faecalis), Listeria monocytogenes, Staphylococcus spp. (koagulazootritsatelny метициллинчувствительные / moderately sensitive strains), including Staphylococcus aureus (metitsillinchuvstvitelny strains), Staphylococcus epidermidis (metitsillinchuvstvitelny strains), Staphylococcus spp. (leykotoksinsoderzhashchy); Streptococcus spp. groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae (пенициллинчувствительные / moderately sensitive/resistant strains), Streptococcus pyogenes, Streptococcus of the viridans group (пенициллинчувствительные / resistant strains).

Aerobic gram-negative microorganisms: Acinetobacter spp. (including Acinetobacter baumannii), Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter agglomerates, Enterobacter spp. (including Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (ампициллинчувствительные / resistant strains), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Moraxella catarrlialis (which are producing and not producing some beta lactamazu strains), Morganella morganii, Neisseria gonorrlioeae (which are producing and not producing a penicillinase strains), Neisseria meningitidis, Pasteurella spp. (and that number of Pasteurella canis, Pasteurella dagmatis, Pasteurella multocida), Proteus mirabilis, Proteus vulgaris, Providencia spp. (including Providencia rettgeri, Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa), Serratia spp. (including Serratia marcescens), Salmonella spp.

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

Other microorganisms: Bartonella spp. Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella spp. (including Legionella pneumophila), Mycobacterium spit (including Mycobacterium leprae, Mycobacterium tuberculosis), Mycoplasma hominis, Mycoplasma pneumoniae, Rickettsia spp., Ureaplasma urealylicum.

Moderately sensitive microorganisms (the minimum overwhelming concentration more or is equal to 8 mg/l):

Aerobic gram-positive microorganisms: Corynebacterium urealylicum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis (metitsillinrezistentny strains), Staphylococcus haemolyticus (metitsillinrezistentny strains).

Aerobic gram-negative microorganisms: Campylobacter jejuni, Campylobacter coli. Anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Steady microorganisms (the minimum overwhelming concentration more or is equal to 8 mg/l):

Aerobic gram-positive microorganisms: Staphylococcus aureus (metitsillinrezistentny strains), other Staphylococcus spp. (koagulazootritsatelny metitsillinrezistentny strains).

Aerobic gram-negative microorganisms: Alcaligenes xylosoxidans.

Anaerobic microorganisms: Bacteroides thetaiotaomicron.

Other microorganisms: Mycobacterium avium.

Clinical performance (efficiency in clinical trials at the infections caused by the listed below microorganisms):
- aerobic gram-positive microorganisms: Enterococcus faecalis. Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes;

- aerobic gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli. Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens;

- other microorganisms: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Pharmacokinetics. At intake it is quickly and almost completely soaked up (meal influences the speed and completeness of absorption a little). Bioavailability - 99%. At a single dose of 500 mg the maximum concentration is reached within 1-2 hours and makes 5.2 ± 1.2 mkg/ml. At a renal failure reduction of clearance of a levofloksatsin and its removal by kidneys depends on extent of decrease in the clearance of creatinine (CC). At KK of 50-80 ml/min. the elimination half-life (T1/2) makes 9 h at KK of 20-40 ml/min. T1/2 makes 27 h, at KK less than 20 ml/min. of T1/2 make 35 h.

Communication with proteins of plasma - 30-40%. Well gets into bodies, fabrics and liquids of an organism: lungs, mucous membrane of bronchial tubes, phlegm, bodies of urinogenital system, polymorphonuclear leukocytes, alveolar macrophages.

In a liver a small part is oxidized and/or deacetylated. Renal clearance - 85% of the general clearance. An elimination half-life - 6-8 h. It is brought out of an organism preferential by kidneys (by glomerular filtering and canalicular secretion) and intestines. Less than 5% of a levofloksatsin are excreted in the form of metabolites.

Indications to use:

The infections caused by activators, sensitive to a levofloksatsin:
- lower respiratory tracts (exacerbation of chronic bronchitis, community-acquired pneumonia);

- ENT organs (acute sinusitis);

- urinary tract and kidneys (including acute pyelonephritis);

- skin and soft tissues (the suppurated atheromas, abscess, furuncles);

- tuberculosis (complex therapy of drug resistant forms);

- chronic bacterial prostatitis.

Route of administration and doses:

Inside, to food or in a break between meals, without chewing, washing down with enough liquid. The mode of dosing is defined by character and weight of an infection, and also sensitivity of the estimated activator. Duration of treatment depends on the course of a disease. Considering that bioavailability of a levofloksatsin at reception of a levofloksatsin is equal in tablets to 99-100%, in case of transfer of the patient from intravenous infusion of a levofloksatsin on reception of tablets it is necessary to continue treatment in the same dose which was applied at intravenous infusion.

At acute sinusitis - on 500 mg of 1 times a day - 10-14 days.

At an exacerbation of chronic bronchitis - on 500 mg of 1 times a day - 7-10 days.

At community-acquired pneumonia - on 500 mg of I-2 times a day - 7-14 days.

At uncomplicated infections of urinary tract - on 250 mg of 1 times a day - 3 days.

At the complicated infections of urinary tract - on 500 mg of the I times a day - 7-14 days.

At pyelonephritis - 500 mg of 1 times a day-7-10 days.

At infections of skin and soft tissues - inside on 500 mg 1-2 times a day - 7-14 days.

At chronic bacterial prostatitis - on 500 mg of 1 times in sou weave - 28 days.

At complex treatment of drug resistant forms of tuberculosis - but 500 mg 1-3 times a day - up to 3 months.

The dosing mode at patients with an impaired renal function

At treatment of patients with an impaired renal function the drug dose decline is required (see the table below).

Clearance creatinine	Dosing mode
	250 mg / 24 hour.	500 mg / 24 hour.	500 mg / 12 hour.
	first dose: 250 mg	first dose: 500 mg	first dose: 500 mg
50 g - 20 ml/min.	then: on 125 mg / 24 hour.	then: 250 mg / 24 hour.	then: 250 mg / 12 hour.
19g10 ml/min.	then: on 125 mg / 48 hour.	then: 125 mg / 24 hour.	then: 125 mg / 12 hour.
<10 ml/min. (including a hemodialysis and PAPD1)	then: on 125 mg / 48 hour.	then: 125 mg / 24 hour.	then: 125 mg / 24 hour.

1 After a hemodialysis or the continuous out-patient peritoneal dialysis (COPPD) introduction of additional doses is not required.

The dosing mode at patients with abnormal liver functions. At an abnormal liver function correction of the mode of dosing as levofloxacin is only slightly metabolized in a liver is not required.

The dosing mode at patients of advanced age. Patients of advanced age do not require correction of the mode of dosing, except for cases of decrease in clearance of creatinine to 50 ml/min. and less.

Features of use:

After normalization of body temperature it is recommended to continue treatment not less than 48-78 h.

At use of a levofloksatsin cases of development of a photosensitization are noted. For prevention of its development patients are not recommended to be exposed to power solar or artificial ultra-violet irradiation during treatment and within 48 hours after the therapy termination.

At emergence of signs of a tendinitis levofloxacin is immediately cancelled.

The hospital infections caused by a pyocyanic stick (Pseudomonas aeruginosa) can demand the combined treatment. Prevalence of the acquired resistance of strains of microorganisms can change depending on the geographical region and eventually. In this regard information on resistance to a levofloksatsin in the specific country is required. Establishment of the microbiological diagnosis with allocation of the activator and definition of its sensitivity to a levofloksatsin is required.

There is a high probability that Staphylococcus aureus (metitsillinrezistentny strains) will be resistant to ftorkhinolona, including levofloxacin. Therefore levofloxacin is not recommended for treatment of Staphylococcus aureus (metitsillinrezistentny strains) established or assumed infections, caused if laboratory analyses did not confirm sensitivity of this microorganism to a levofloksatsin.

As well as at use of other antibiotics, use of a levofloksatsin, especially for a long time, can lead to the strengthened reproduction of microorganisms, insensitive to it (bacteria and mushrooms) that can cause changes of microflora which normal is present at the person, and, respectively, мо) to lead Siberian salmons to development of superinfection. Therefore during treatment it is obligatory to carry out repeated assessment of a condition of the patient and in case of development of superinfection it is necessary to take the appropriate measures.

If the patient has a diarrhea on the foyer of reception of a levofloksatsin, drugs braking an intestines peristaltics are contraindicated as it must be kept in mind a possibility of development of pseudomembranous colitis. Treatment by antibacterial agents leads to modification of normal flora of a large intestine and can lead to the strengthened growth of clostridiums. If the diagnosis "pseudomembranous colitis" is established, it is necessary to cancel levofloxacin and to begin the corresponding treatment.

Ftorkhinolona, including levofloxacin, can block neuromuscular activity and increase muscular weakness at patients with a pseudoparalytic myasthenia (myasthenia gravis). In the post-marketing period adverse reactions, including the pulmonary insufficiency which demanded carrying out artificial ventilation of the lungs, and death which were associated using ftorkhinolon at patients with a pseudoparalytic myasthenia were observed. Use of a levofloksatsin for patients with the established diagnosis of myasthenia gravis is not recommended.

It must be kept in mind that at patients with damage of a brain in the anamnesis (a stroke, a severe injury) development of spasms is possible, at insufficiency glyukozo-6-fosfatdegidrogenazy - risk of development of hemolysis.

At the heavy community-acquired pneumonia caused by Streptococcus pneumoniae, levofloxacin can not give optimum therapeutic effect.

At the patients applying ftorkhinolona, including levofloxacin cases of the touch and sensomotor axonal polyneuropathy affecting small and (or) large axons, and leading to paresthesia, a giposteziya, a dizesteziya and weakness are registered. Symptoms can soon be shown after the beginning of use and to be irreversible. If at the patient neuropathy symptoms, including pain, burning, a pricking, numbness and (or) weakness or other disturbances of sensitivity, including tactile, painful, temperature, vibration sensitivity and feeling of situation develop, use of the drug Levofloxacin needs to be stopped immediately.

Patients should stop immediately administration of drug and to see a doctor at development of serious, zhizneugrozhayushchy reactions of hypersensitivity, and also at the first manifestations from skin or mucous membranes.

It was reported about cases of development of psychotic reactions which seldom or never progressed before development of suicide thoughts and behavior disorders with causing to themselves harm. In case of the similar phenomena it is necessary to stop reception of a levofloksatsin. It is necessary to apply with care levofloxacin to patients with psychoses or to the patients having mental diseases in the anamnesis.

In cases of development of any vision disorders immediate consultation of the ophthalmologist is necessary.

As levofloxacin is excreted mainly through kidneys, obligatory control of function of kidneys, and also correction of the mode of dosing is required from patients with a renal failure (see the section "Route of Administration and Doses"). At treatment of patients of advanced age it must be kept in mind that at patients of this group renal failures are often noted (see the section "Route of Administration and Doses"). It was reported about cases of development of a hepatic necrosis, including development of a fatal liver failure at use of a levofloksatsin, mainly, at patients with serious basic diseases, for example, with sepsis. In case of signs and symptoms of damage of a liver, such as anorexia, jaundice, urine darkening, itch and abdominal pain, it is necessary to stop treatment by drug. It was reported about very exceptional cases of lengthening of an interval of QT at the patients receiving ftorkhinolona including levofloxacin.

At use of ftorkhinolon, including levofloxacin, it is necessary to be careful at female patients, at patients of advanced age, at patients with not corrected electrolytic disturbances (with a hypopotassemia, a hypomagnesiemia), patients with the known risk factors have lengthenings of an interval of QT: with a syndrome of inborn lengthening of an interval of QT; with heart diseases (heart failure, a myocardial infarction, bradycardia); at a concomitant use of the medicines capable to extend an interval of QT, such as antiarrhytmic means of IA and the III class, tricyclic antidepressants, macroleads, neuroleptics.

There were messages on cases of development of a hyperglycemia and a hypoglycemia, usually at the patients with a diabetes mellitus receiving at the same time treatment by peroral hypoglycemic drugs (for example, Glibenclamidum) or insulin drugs, at use of a levofloksatsin, and also about cases of development of a hypoglycemic coma.

At use of a levofloksatsin it is necessary to consider what can give definition of opiates in urine to false positive results which should be confirmed with more specific methods.

Levofloxacin can inhibit growth of Mycobacterium tuberculosis and result further in false-negative results of the bacteriological diagnosis of tuberculosis.

Influence on ability to manage vehicles and mechanisms. During treatment it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. It is necessary to take potentiality of development of such side effects into account as dizziness, вертиго, drowsiness and visual disturbances. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the types of activity stated above.

Side effects:

From the alimentary system: nausea, vomiting, diarrhea (including е кровыо), digestion disturbance, a loss of appetite, an abdominal pain, pseudomembranous colitis, increase in activity of "hepatic" transaminases, increase in activity of an alkaline phosphatase and gamma глутамилтрансферазы, a hyperbilirubinemia, hepatitis, a heavy liver failure, including cases of development of an acute liver failure, sometimes with a fatal outcome, especially at patients with a serious basic disease (for example, at patients with sepsis), dysbacteriosis, a meteorism, a lock, pancreatitis, stomatitis, jaundice.

From cardiovascular system: a lowering of arterial pressure, a vascular collapse, tachycardia, lengthening of an interval of QT, a heart consciousness, ventricular disturbances of a rhythm, ventricular tachycardia, ventricular tachycardia like "pirouette" which can lead to a cardiac standstill, benign intracranial hypertensia.

From a metabolism: a hypoglycemia (increase in appetite, the increased sweating), a hypoglycemic coma, a hyperglycemia.

From a nervous system: a headache, dizziness, weakness, a syncope, a soplivost, sleeplessness, sleep disorders, nightmares, a tremor, concern, paresthesias, fear, hallucinations, confusion of consciousness, anorexia, a depression, motive frustration, spasms, peripheral touch neuropathy and peripheral sensory-motor neuropathy, dyskinesia, extrapyramidal frustration, alarm, agitation, paranoia, disturbances of mentality with behavior disorders with causing to harm, including suicide thoughts and suicide attempts.

From sense bodys: вертиго, a ring in ears, vision disorders, decrease in hearing, sense of smell, flavoring and tactile sensitivity, passing loss of sight, a hearing loss, a dysgeusia, loss of flavoring feelings, a parosmiya, including loss of sense of smell.

From a musculoskeletal system: arthralgia, muscular weakness, mialgiya, rupture of sinews, tendinitis, rupture of sheaves, rupture of muscles, arthritis.

From an urinary system: giperkreatininemiya, intersticial nephrite, acute renal failure.

From bodies of a hemopoiesis: eosinophilia, hemolitic anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, hemorrhages.

Allergic reactions: photosensitization, rash, itch and dermahemia, cutaneous dropsy and mucous membranes, small tortoiseshell, exudative mnogoformny erythema, malignant exudative erythema (Stephens-Johnson's syndrome), toxic epidermal necrolysis (Lyell's disease), bronchospasm, suffocation, Quincke's disease, anaphylactoid shock, acute anaphylaxis, allergic pneumonitis, leykotsitoklastichesky vasculitis.

Others: an adynamy, an asthma, an aggravation porphyrite a hyperhidrosis, рабдомиолиз, persistent fever, development of superinfection, development of resistance of pathogenic microorganisms, pain (including a dorsodynia, breasts and extremities).

Interaction with other medicines:

Levofloxacin increases a cyclosporine elimination half-life by 33%. As this increase is clinically insignificant, dose adjustment of cyclosporine at its simultaneous use with levofloksatsiny is not required.

Effect of a levofloksatsin reduce medicines, the oppressing motility of intestines, magnesium - and aluminum-bearing antiacid medicines and salts of iron (the break between reception not less than 2 h is necessary).

Effect of the drug Levofloxacin is considerably weakened at simultaneous use of a sukralfat (means for protection of a mucous membrane of a stomach). The patients charging levofloxacin and сукральфат are recommended to accept сукральфат in 2 hours after reception of a levofloksatsin.

Non-steroidal anti-inflammatory drugs, theophylline increase risk of development of spasms, glucocorticosteroids increase risk of a rupture of sinews.

At simultaneous use with the indirect anticoagulants derivative of coumarin, control of the international normalized relation is necessary, at simultaneous use of a levofloksatsin and indirect anticoagulants increase in prothrombin time / the international normalized relation and/or development of bleeding including heavy was observed.

Simultaneous use of a levofloksatsin and peroral hypoglycemic means or insulin can lead to development of a hypoglycemia or hyperglycemia. Careful monitoring of concentration of glucose in blood is recommended.

At simultaneous use of the medicines breaking renal canalicular secretion of a levofloksatsin such as пробенецид and циметидип, it is necessary to be careful, especially at patients with a renal failure. Tsimetidip and пробенецид slow down removal of a levofloksatsin for 24% and 34%, respectively. It is improbable that it can have clinical value at normal function of kidneys.

Levofloxacin, as well as other ftorkhinolona, has to be applied with care at the patients receiving the drugs extending QT interval (for example, antiarrhythmic drugs of the class IA and III, tricyclic antidepressants, macroleads, neuroleptics).

At simultaneous use диданозин (only dosage forms containing in quality of the buffer aluminum or magnesium) absorption reduces and weakens effect of a levofloksatsin (the interval between administrations of drugs has to make not less than 2 h). At simultaneous use of salt of calcium pases absorption of a levofloksatsin slightly influence.

Others. Results of the conducted kliniko-pharmacological researches on studying of possible pharmacokinetic interactions of a levofloksatsin with digoxin, glibenclamide, ranitidine, warfarin showed that at simultaneous use with these drugs the pharmacokinetics of a levofloksatsin does not change sufficiently that it had clinical value.

Contraindications:

Hypersensitivity to a levofloksatsin, other hinolona, other components of drug, epilepsy, damage of sinews at earlier carried out treatment of a hinolonama, pregnancy, the breastfeeding period, age up to 18 years, a lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption, a myasthenia гравис (myasthenia gravis).

With care. Advanced age (high probability of existence of the accompanying depression of function search), deficit glyukozo-6-fosfatdegidrogenazy; at patients with psychoses or at the patients having mental diseases in the anamnesis; at patients with heavy undesirable reactions to other ftorkhinolona, such as heavy neurologic reactions; at the patients predisposed to development of spasms (at patients with the previous damages of the central nervous system; at the patients who are at the same time receiving the drugs reducing a threshold of convulsive readiness of a brain such as фенбуфен, theophylline); at patients with a renal failure; patients with the known risk factors for lengthening of an interval have QT: at patients of advanced age, at patients is a female, at patients with not adjusted electrolytic disturbances (for example, with a hypopotassemia, a hypomagnesiemia), with a syndrome of inborn lengthening of an interval of QT, with heart diseases (heart failure, a myocardial infarction, bradycardia), at a concomitant use of the medicines capable to extend QT interval (antiarrhytmic means of the class IA and III, tricyclic antidepressants, macroleads, neuroleptics); at the patients with a diabetes mellitus receiving peroral hypoglycemic drugs, for example, glibenclamide or drugs of insulin (the risk of development of a hypoglycemia increases).

Overdose:

Overdose symptoms are shown by the drug Levofloxacin from the central nervous system: consciousness disturbance, including confusion of consciousness, dizziness, spasms, hallucinations, a tremor. Besides, it can be noted: lengthening of an interval of QT, gastrointestinal frustration (for example, nausea) and erosive damages of a mucous membrane of digestive tract.

Symptomatic treatment. In case of overdose of tablets of Levofloksatsin the gastric lavage and introduction of antacids for protection mucous a stomach, and also carrying out monitoring of the electrocardiogram is shown. Levofloxacin is not removed by means of dialysis. The specific antidote does not exist.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 250 mg, 500 mg. Packaging: on 5 or 10 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. On 50 or 100 tablets in bank of polymeric. On 1 blister strip packaging or 1 bank polymeric together with the application instruction in a cardboard pack.