INSTRUCTIONS
on medical use of the drug

Registration number: P N012034 / 01

Trade name of the drug: Avelox ®

International Nonproprietary Name (INN): moxifloxacin

Dosage Form : film coated tablets

Composition: 1 tablet contains:
Active substance: moxifloxacin hydrochloride 436.8 mg, equivalent to 400.0 mg moxifloxacin.
Excipients: microcrystalline cellulose (136.0 mg), sodium croscarmellose (32.0 mg), lactose monohydrate (68.0 mg), magnesium stearate (6.0 mg), film cover  - hypromellose (9.0 - 12.6 mg), iron dye red oxide (0.3 - 0.42 mg), macrogol 4000 (3.0 - 4.2 mg), titanium dioxide (2.7 - 3, 78 mg).

Description: Pink matte oblong biconvex with a facet tablets, film-coated, with an engraving "BAYER" on one side and "M400" on the other side.

Pharmacotherapeutic group: antimicrobial agent - fluoroquinolone
ATX code  J01MA14

pharmachologic effect
Pharmacodynamics
Mechanism of action
  Moxifloxacin - a broad-spectrum bactericidal antibacterial drug, 8-methoxyfluoroquinolone. The bactericidal effect of the drug is due to inhibition of bacterial topoisomerases II and IV, which leads to disruption of the replication, repair and transcription of the biosynthesis of microbial cell DNA and, as a result, the death of microbial cells.
  The minimum bactericidal concentrations of the drug are generally comparable to its minimum inhibitory concentrations. Mechanisms of resistance
  The mechanisms that lead to the development of resistance to penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not affect the antibacterial activity of moxifloxacin. Cross-resistance between these groups antibacterial drugs and moxifloxacin is not marked. So far, there have also been no cases of plasmid resistance. The overall frequency of the development of resistance is very small (10 -7 - 10 -10). Resistance to moxifloxacin develops slowly through multiple mutations. Repeated exposure of moxifloxacin to microorganisms at concentrations below the minimum inhibitory concentration (MIC) is accompanied by only a slight increase in MIC. There are cases of cross-resistance to quinolones. However, some gram-positive and anaerobic microorganisms that are resistant to other quinolones retain sensitivity to moxifloxacin.
  It has been established that the addition of the methoxy group to the moxifloxacin structure in the C8 position increases the activity of moxifloxacin and reduces the formation of resistant mutant strains of gram-positive bacteria. The addition of the bicyclo-amine group in position C7 prevents the development of active efflux, the mechanism of resistance to fluoroquinolones.
  Moxifloxacin in vitro  active against a wide range of gram-negative and gram-positive microorganisms, anaerobes, acid-resistant bacteria and atypical bacteria, such as Mycoplasma spp., Chlamydia spp., Legionella spp.as well as bacteria resistant to ß-lactam and macrolide antibiotics.
Effect on human intestinal microflora
  In two studies conducted on volunteers, the following changes in intestinal microflora were observed after oral administration of moxifloxacin: a decrease in concentrations Escherichia coli, Bacillus spp., Bacteroides vulgatus, Enterococcus spp., Klebsiella spp., As well as anaerobes Bifidobacterium spp., Eubacterium spp., Peptostreptococcus spp. These changes were reversible within two weeks. Toxins Clostridium difficile  not found.
In vitro sensitivity testing
  The spectrum of antibacterial activity of moxifloxacin includes the following microorganisms:

For certain strains, the distribution of acquired resistance may vary depending on the geographic region and over time. In this regard, when testing the sensitivity of the strain, it is desirable to have local information on resistance, especially in the treatment of severe infections. If in patients treated in a hospital, the value of AUC / MIC 90 exceeds 125, and C max / MIC 90 is between 8-10, then this suggests a clinical improvement. In outpatient patients, the values ​​of these surrogate parameters are usually less: AUC / MIC 90\u003e 30-40

Pharmacokinetics
Absorption and bioavailability
When taken orally, moxifloxacin is absorbed quickly and almost completely. Absolute bioavailability is about 91%.
  The pharmacokinetics of moxifloxacin when taken in a dose of 50 to 1200 mg once, and 600 mg / day for 10 days is linear. The equilibrium state is reached within 3 days.
  After a single application of 400 mg of moxifloxacin, the maximum concentration (C max) in the blood is reached within 0.5-4 hours and amounts to 3.1 mg / l. After ingestion of 400 mg of moxifloxacin 1 time per day, Css max and Css mim are 3.2 mg / l and 0.6 mg / l, respectively.
  When taking moxifloxacin together with food, there is a slight increase in the time to reach C max (by 2 h) and a slight decrease in C max (approximately 16%), while the duration of absorption does not change. However, these data have no clinical significance, and the drug can be used regardless of the meal.
Distribution
  Moxifloxacin is rapidly distributed in tissues and organs and binds to blood proteins (mainly albumin) by about 45%. The volume of distribution is approximately 2 l / kg.
  High concentrations of the drug, exceeding those in the blood plasma, are created in the lung tissue (including epithelial fluid, alveolar macrophages), in the nasal sinuses (maxillary and ethmoid sinuses), in nasal polyps, in the foci of inflammation (in the contents of the skin lesions). In the interstitial fluid and in saliva, the drug is determined in a free, non-protein form, at a concentration higher than in the blood plasma. In addition, high concentrations of the drug are determined in the tissues of the abdominal cavity, peritoneal fluid and female genitals.
Metabolism
  Moxifloxacin undergoes biotransformation of the 2nd phase and is excreted from the body by the kidneys, as well as through the intestines, both in unchanged form and in the form of inactive sulpho compounds (Ml) and glucuronides (M2). Moxifloxacin is not biotransformed by the microsomal cytochrome P450 system. Metabolites Ml and M2 are present in plasma at concentrations lower than the parent compound. According to the results of preclinical studies, it was proved that these metabolites do not have a negative impact on the body in terms of safety and tolerability.
Removal
The half-life of the drug is approximately 12 hours. The average total clearance after administration at a dose of 400 mg is 179-246 ml / min. Renal clearance is 24-53 ml / min. This indicates a partial tubular reabsorption of the drug.
  The mass balance of the starting compound and the metabolites of the 2nd phase is approximately 96-98%, which indicates the absence of oxidative metabolism. About 22% of the single dose (400 mg) is excreted unchanged by the kidneys, about 26% through the intestines.

Pharmacokinetics in different groups of patients
Age, Gender and Ethnicity
  Age and gender differences in the pharmacokinetics of moxifloxacin have not been established. There were no clinically significant differences in the pharmacokinetics of moxifloxacin in patients of different ethnic groups.
Children
  The pharmacokinetics of moxifloxacin in children has not been studied.
Renal failure
  There were no significant changes in the pharmacokinetics of moxifloxacin in patients with impaired renal function (including patients with creatinine clearance<30 мл/мин/ 1,73 м 2), находящихся на непрерывном гемодиализе и длительном амбулаторном перитонеальном диализе.
Liver dysfunction
  There were no significant differences in the concentration of moxifloxacin in patients with impaired liver function (classes A, B, C according to the Child-Pugh classification) compared with healthy volunteers and patients with normal liver function (for use in patients with liver cirrhosis, see also “Special instructions ").

Indications for use
  Infectious inflammatory diseasescaused by microorganisms sensitive to moxifloxacin:

• Acute sinusitis,
• Exacerbation of chronic bronchitis,
• Uncomplicated infections of the skin and subcutaneous structures,
• Community-acquired pneumonia, including community-acquired pneumonia, the causative agents of which are strains of microorganisms with multiple resistance to antibiotics *,
• Complicated infections of the skin and subcutaneous structures (including an infected diabetic foot),
• Complicated intra-abdominal infections, including polymicrobial infections, including intraperitoneal abscesses,
• Uncomplicated inflammatory diseases of the pelvic organs (including salpingitis and endometritis).
• Streptococcus pneumoniae  multiple antibiotic resistances include penicillin-resistant strains and strains resistant to two or more antibiotics from groups such as penicillins (with MIC\u003e 2 μg / ml), 2nd generation cephalosporins (cefuroxime), macrolides, tetracyclines and trimethoprim / sulfamethoxazole.

Contraindications

• Hypersensitivity to moxifloxacin, other quinolones or any other component of the drug,
• Age 18 years,
• Pregnancy and breastfeeding period,
• A history of tendon pathology developed as a result of quinolone treatment with antibiotics.
• In preclinical and clinical studies after the administration of moxifloxacin, a change in the electrophysiological parameters of the heart was observed, expressed in prolongation of the QT interval. In this regard, the use of moxifloxacin is contraindicated in patients of the following categories: congenital or acquired documented lengthening of the QT interval, electrolyte disturbances, especially uncorrected hypokalemia; clinically significant bradycardia; clinically significant heart failure with a reduced left ventricular ejection fraction; history of rhythm disturbances, accompanied by clinical symptoms.
• Moxifloxacin should not be used with other drugs, extending the QT interval.
• Due to the presence of lactose in the preparation, its use is contraindicated in case of congenital lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
• Due to the limited amount of clinical data, the use of moxifloxacin is contraindicated in patients with impaired liver function (Child-Pugh class C) and in patients with increased transaminases more than five times higher than the upper limit of normal.

Use during pregnancy and during breastfeeding
  The safety of moxifloxacin during pregnancy has not been established and its use is contraindicated. Cases of reversible damage to the joints in children receiving certain quinolones have been described, but no manifestations of this effect have been reported in the fetus (when applied by the mother during pregnancy).
  Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.
Like other quinolones, moxifloxacin causes cartilage damage to large joints in premature animals. In preclinical studies found that a small amount of moxifloxacin is released into breast milk. There are no data on its use in women during lactation. Therefore, the appointment of moxifloxacin during breastfeeding is contraindicated.

Dosage and administration
  Recommended dosing regimen of moxifloxacin: 400 mg (1 tablet) 1 time per day for the infections indicated above. Do not exceed the recommended dose.
  Tablets should be swallowed whole, without chewing, with a sufficient amount of water, regardless of the meal.
Duration of treatment
  The duration of treatment is determined by the location and severity of the infection, as well as the clinical effect:

• Exacerbation of chronic bronchitis: 5-10 days,
• Acute sinusitis: 7 days,
• Uncomplicated infections of the skin and subcutaneous structures: 7 days,
• Community-acquired pneumonia: the total duration of the step therapy (intravenous administration followed by ingestion) is 7-14 days,
• Complicated infections of the skin and subcutaneous structures: the total duration of the stepwise therapy with moxifloxacin (intravenous administration followed by ingestion) is 7-21 days,
• Complicated intra-abdominal infections: the total duration of the step therapy (intravenous administration followed by ingestion) is 5-14 days,
• Uncomplicated inflammatory diseases of the pelvic organs - 14 days.

Side effect
Evidence of adverse reactions recorded when using moxifloxacin 400 mg (orally, with stepwise therapy [intravenous administration of the drug followed by ingestion] and only intravenously) is obtained from clinical studies and post-marketing messages (in italics). Adverse reactions listed in the group “often” occurred with a frequency below 3%, with the exception of nausea and diarrhea.
  In each frequency band unwanted drug reactions  listed in descending order of importance. The frequency is determined as follows:
  often (from\u003e 1/100 to<1/10),
  infrequently (from\u003e 1/1000 to<1/100),
  rarely (from\u003e 1/10000 to<1/1000),
  very rarely (<1/10000).

Overdose
  There is limited evidence of an overdose of moxifloxacin. No side effects were noted with the use of moxifloxacin at a dose of up to 1200 mg once and 600 mg for 10 days or more. In case of overdose, you should focus on the clinical picture and carry out symptomatic supportive therapy with ECG monitoring.

Interaction with other drugs
  When combined with atenolol, ranitidine, calcium supplements, theophylline, oral contraceptives, glibenclamide, itraconazole, digoxin, morphine, probenecid (confirmed the absence of clinically significant interaction with moxifloxacin) dose adjustment is not required.
Antacids, Multivitamins and Minerals
  Acceptance of moxifloxacin simultaneously with antacid agents, multivitamins and minerals can lead to impaired absorption of moxifloxacin, due to the formation of chelate complexes with polyvalent cations contained in these preparations. As a result, plasma concentration of moxifloxacin may be significantly lower than desired. In this regard, antacid drugs, antiretroviral drugs (for example, didanosine) and other drugs containing magnesium or aluminum, sucralfate and other drugs containing iron or zinc should be used at least 4 hours before or 4 hours after ingestion moxifloxacin.
Warfarin
When combined with warfarin, the prothrombin time and other clotting parameters do not change.
Change in mho value. In patients who received anticoagulants in combination with antibiotics, including moxifloxacin, there have been cases of increased anticoagulant activity of anticoagulant drugs. Risk factors are the presence of an infectious disease (and associated inflammatory process), age and general condition of the patient. Although no interaction between moxifloxacin and warfarin has been identified, patients receiving combined treatment with these drugs need to monitor MHO and, if necessary, adjust the dose of indirect anticoagulants.
Digoxin
  Moxifloxacin and digoxin does not have a significant effect on the pharmacokinetic parameters of each other. When prescribing repeated doses of moxifloxacin, the maximum concentration of digoxin increased by approximately 30%, while the area under the concentration-time curve (AUC) and the minimum concentration of digoxin did not change.
Activated carbon
  With simultaneous use of activated carbon and moxifloxacin orally at a dose of 400 mg, the systemic bioavailability of the drug is reduced by more than 80% as a result of inhibition of its absorption. In case of overdose, the use of activated carbon in the early stage of absorption prevents the further increase in systemic exposure.

special instructions
  In some cases, after the first use of the drug may develop hypersensitivity and allergic reactions, which should immediately inform the doctor. Very rarely, even after the first use of the drug, anaphylactic reactions can progress to life-threatening anaphylactic shock. In these cases, treatment with moxifloxacin should be canceled and the necessary therapeutic measures (including anti-shock) should be carried out.
  When using moxifloxacin, some patients may experience a prolongation of the QT interval. When analyzing the ECG obtained during clinical trials, the corrected QT interval was 6 msec +/- 26 msec, 1.4% compared to baseline. Since women have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients are also more susceptible to drugs that affect the QT interval.
The degree of prolongation of the QT interval may increase with an increase in the concentration of the drug; therefore, it should not exceed the recommended one. However, in patients with pneumonia, a correlation between plasma concentration of moxifloxacin and prolongation of the QT interval was noted. Lengthening the QT interval is associated with an increased risk of ventricular arrhythmias, including polymorphic ventricular tachycardia. None of the 9,000 patients treated with moxifloxacin had cardiovascular complications and deaths associated with prolongation of the QT interval. However, in patients with conditions predisposing to arrhythmias, the use of moxifloxacin may increase the risk of developing ventricular arrhythmias.
  In this regard, moxifloxacin should not be prescribed to patients with established prolongation of the QT interval, patients with uncorrected hypokalemia, as well as patients who receive class I antiarrhythmic drugs (quinidine, procainamide) and class III (amiodarone, sotalol, ibutilide).
  Due to the risk of an additive effect on the QT interval, moxifloxacin should not be administered concurrently with those extending to the QT (cisapride, erythromycin, antipsychotic drugs, tricyclic antidepressants), patients with conditions that are prone to arrhythmias, such as a clinically significant bradycardia, such as a clinically significant bradycardia. also to those patients with cirrhosis of the liver, in whom the risk of developing a prolonged QT interval cannot be excluded, especially for women and elderly patients (since these categories of patients are more sensitive to flax for drugs that extend the QT interval).
  When taking moxifloxacin, cases of fulminant hepatitis have been reported, potentially leading to the development of liver failure (including fatal cases) (see the “Side effect” section). The patient should be informed that if symptoms of liver failure appear, it is necessary to consult a doctor before continuing treatment with moxifloxacin.
  When taking moxifloxacin, cases of bullous skin lesions have been reported (Stevens-Johnson syndrome, toxic epidermal necrolysis). The patient should be informed that if symptoms of lesions of the skin or mucous membranes appear, it is necessary to consult a doctor before continuing treatment with moxifloxacin.
The use of quinolone drugs is associated with a possible risk of seizures. Moxifloxacin should be used with caution in patients with diseases of the central nervous system and with conditions suspicious of involvement of the central nervous system, predisposing to seizures or lowering the threshold of seizure activity.
  The use of broad-spectrum antibacterial drugs, including moxifloxacin, is associated with the risk of developing pseudomembranous colitis associated with antibiotics. This diagnosis should be kept in mind in patients who have severe diarrhea during treatment with moxifloxacin. In this case, appropriate therapy should be prescribed immediately. Drugs that inhibit intestinal motility are contraindicated in the development of severe diarrhea.
  Moxifloxacin should be used with caution in patients with myasthenia gravis due to possible exacerbation of the disease.
  Tendinitis and tendon rupture may develop with quinolone therapy, including moxifloxacin, especially in the elderly and patients receiving glucocorticosteroids. At the first symptoms of pain or inflammation at the site of injury, the drug should be stopped and the affected limb unloaded. When quinolones are used, photosensitivity reactions are noted. However, when conducting preclinical and clinical studies, as well as when applying moxifloxacin in practice, photosensitivity reactions were not observed. However, patients receiving moxifloxacin should avoid exposure to direct sunlight and ultraviolet light.
  The use of the drug in the form of tablets for oral administration is not recommended in patients with complicated inflammatory diseases of the pelvic organs (for example, associated with tubo-ovarian or pelvic abscesses).
  Patients who follow a low salt diet (with heart failure, kidney failure, with nephrotic syndrome) should take into account that sodium chloride solution is in the solution for infusions.
Dairy products and food intake
  Moxifloxacin absorption does not change with the simultaneous ingestion of food (including dairy products). Moxifloxacin can be taken regardless of the meal.

Influence on ability to steer the car and moving mechanisms
Fluoroquinolones, including moxifloxacin, can impair the ability of patients to drive and engage in other potentially hazardous activities that require increased attention and quickness of psychomotor reactions, due to the effect on the central nervous system.

Release form
  Tablets, film coated, 400 mg.
  On 5 tablets in the blister from aluminum foil and PA / Al / PVC or from aluminum foil and 1111. On 1 or 2 blisters together with the application instruction in a cardboard pack, or
  On 7 tablets in the blister from aluminum foil and PA / Al / PVC or aluminum foil and software. On 1 blister together with the application instruction in a cardboard pack.

Shelf life
  5 years. Do not use after the expiration date printed on the package.

Storage conditions
  At a temperature not higher than 25 ° С.
  Keep out of the reach of children.

Vacation conditions
  On prescription.

Legal entity in whose name the registration certificate is issued:
  Bayer Pharma AG, Müllerstrasse 178, 13353 Berlin, Germany
  Bayer Pharma AG, Mullerstrasse 178, 13353 Berlin, Germany

Manufacturer:
  Bayer Pharma AT, D-51368, Leverkusen, Germany
  Bayer Pharma AG, D-51368, Leverkusen, Germany

For more information please contact:
  107113 Moscow, 3rd Rybinskaya st., 18, p. 2.